AIDS: VIRUS- OR DRUG INDUCED?

Contemporary Issues in Genetics and Evolution

VOLUME 5

The titles published in this series are listed at the end of this volume.
AIDS:
Virus- or Drug Induced?

Edited by
PETER H. DUESBERG

Contributions with an asterisk in the table of contents were first published in Genetica, Volume 95 no. 1-3 (1995)

Kluwer Academic Publishers

DORDRECHT/BOSTON/LONDON
Library of Congress Cataloging-in-Publication Data

AIDS : viru~or drug induced? I edited by Peter H. DuesberQ.

p. cm. -- (Contemporary issues in genetlcs and evo!utl0n ; v"
5)
Includes bibliographical references and index.
ISBN-13:978-0-7923-3961-8
1. AIDS (Disease)--Etlo1ogy. I. Duesberg. Peter. II. Series.
RC607.A26A34743 1995
616.97"92071--dc20 95-17475

ISBN-13:978-0-7923-3961-8 e-ISBN-I3:978-94-009-1651-7
DOl: 10.1007/978-94-009-1651-7

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Contents

Foreword by P.H. Duesberg

* E. Papadopulos-Eleopulos, V.F. Turner, I.M. Papadimitriou, D. Causer, B. Hedland-Thomas and

B.A.P. Page, A critical analysis of the mv-T4-cell-AIDS hypothesis 3

* E. Papadopulos-Eleopulos, V.F. Turner, I.M. Papadimitriou and D. Causer, Factor VIII, mv and
AIDS in haemophiliacs: an analysis of their relationship 23

* P.H. Duesberg, Foreign-protein-mediated immunodeficiency in hemophiliacs with and without HIV 49

* V.L. Koliadin, Critical analysis of the current views on the nature of AIDS 69

M. Craddock, Some mathematical considerations on mv and AIDS 89

* B.J. Ellison, A.B. Downey and P.H. Duesberg, HIV as a surrogate marker for drug use: are-analysis
of the San Francisco Men's Health Study 97

M. Craddock, A critical appraisal of the Vancouver men's study Does it refute the drugs/AIDS
hypothesis? 105

P.H. Duesberg and H. Bialy, Duesberg and the right of reply according to Maddox-Nature 111

M. Craddock, mv: Science by press conference 127

* M.D. Zaretsky, AZT toxicity and AIDS prophylaxis: is AZT beneficial for HIV+ asymptomatic
persons with 500 or more T4 cells per cubic millimeter? 131

* D.T. Chiu and P.H. Duesberg, The toxicity of azidothymidine (AZT) on human and animal cells in
culture at concentrations used for antiviral therapy 143

* H.W. Haverkos and D.P. Drotman, Measuring inhalant nitrite exposure in gay men: implications for
elucidating the etiology of AIDS-related Kaposi's sarcoma 151

* K.B. Mullis, A hypothetical disease of the immune system that may bear some relation to the
Acquired Immune Deficiency Syndrome 159

* G.T. Stewart, The epidemiology and transmission of AIDS: a hypothesis linking behavioural and
biological determinants to time, person and place 163

* R.S. Root-Bernstein, Five myths about AIDS that have misdirected research and treatment 185

* R.S. Root-Bernstein and S. Hobbs De Witt, Semen alloantigens and lymphocytotoxic antibodies in
AIDS and ICL 207

* Contributions indicated with an asterisk were first published in Genetica, Volume 95 no. 1-3 (1995).
S.B. Harris, AIDS and good theory-making 231

P.H. Duesberg, How much longer can we afford the AIDS virus monopoly? 241

S. Lang, HIV and AIDS: Have we been misled? Questions of scientific and journalistic responsibility 271

S. Lang, To fund or not to fund, that is the question: proposed experiments on the drug-AIDS
hypothesis To inform or not to inform, that is another question 297

J. Lauritsen, HIV Symposium at AAAS Conference 309

T. Bethell, AIDS and poppers 315

J. Lauritsen, NIDA meeting calls for research into the poppers-Kaposi's sarcoma connection 325

P.E. Johnson, The thinking problem in HIV-science 331

J. Lauritsen, The incidence quagmire 337

C. Farber, The HIV test 343

N. Hodgkinson, Cry, beloved country How Africa became the victim of a non-existent epidemic of
HIVIAIDS 347
P.H. Duesberg (ed.}, AIDS: Virus- or Drug Induced?, 1-2, 1996.
© 1996 Kluwer Academic Publishers.

Foreword

Despite enormous efforts, over 100 000 papers and over $35 billion spent by the US tax payer alone, the mV-AIDS
hypothesis has failed to produce any public health benefits: no vaccine, no effective drug, no prevention, no cure,
not a single life saved (Duesberg, 1992; Benditt & Jasny, 1993; Duesberg, 1994; Fields, 1994; Swinbanks, 1994;
AIDS Weekly, 1995; Farber, 1995). Is our science system to be blamed? Has science failed to reveal the truth about
AIDS?
Science, like the law, serves the community as finder of the truth. The legal system serves to identify and penalize
those who threaten the status quo, the scientific system serves to identify and reward those who advance knowledge
when the status quo fails to produce beneficial results. Both systems use outwardly very similar methods to find
the truth. The law evaluates the performance of a citizen with a jury of citizens who are supposed to consider all
relevant facts without prejudice and are supposed to be free from political and personal bias. Science evaluates the
performance of a given scientist, or group of scientists, by the peer-review system, a jury of peers, who are also
expected to be unprejudiced about the facts and free of political and personal bias.
The community can easily determine if a legal jury fails to be unprejudiced or unbiased. A recent example is the
public pressure that moved the Rodney King trial in Los Angeles in 1992 from a jury in the Simi Valley district,
which had favored white police power over the rights of its black victim, to a jury in another district for a retrial.
Without legal education, the community played a corrective role in finding justice.
However, the community is much less likely to detect bias and prejudice in a scientific jury because it lacks
professional knowledge both of the facts and the politics of science. It assumes that all scientists are virtually free
of bias and eager to advance the frontiers of knowledge if the status quo fails to provide help and health for the
community.
But the public's high confidence in the sciences is not justified for several reasons'
(i) The ability of an individual scientist to find the truth is limited by his or her expertise. A nuclear physicist
will be biased against a coal-powered reactor, and a virologist against non-viral causes of cancer or AIDS.
(ii) In the medical sciences, the primary bias of an individual scientist can be greatly compounded by the collective
power of a reigning orthodoxy. Since nearly all funding for basic and clinical research in medicine comes from one
source, the National Institutes of Health (NIH), the school of thought that succeeds first in winning NIH approval
can quickly seize control of the funding and the publication of all research through the peer- review system. Indeed,
a scientific orthodoxy that depends on NIH funding for its research cannot even afford to tolerate non-conformist
hypotheses, because alternatives that prove successful are inherent threats to the reigning orthodoxy, and the
scientific peers rarely grant a non-conformist a day in court.
Scientific papers submitted for publication are reviewed anonymously by the orthodoxy. And the peers exclude
the applicant when a grant application is reviewed for funding. Unlike the legal system, a'scientific orthodoxy
excludes all outsiders from its juries. Although all grant applications are supposedly directed at the tax payer, who
is addressed by a mandatory non-scientific abstract, not even outside scientists are ever elected for peer review. The
orthodoxy claims that only experts who practice the field can possibly understand how a solution could be found.
In the courts of science the defense selects its own jury.
Since this is not known to the non-scientific community, scientists enjoy the enviable reputation of pursuing
the truth unbiased by political and commercial interests. There is, however, one criterion by which the community
can find out whether its scientists are finding the truth, even without professional knowledge: the ability of these
scientists to produce useful results. And AIDS science has achieved an outstanding record of non-productivity that
even the most dedicated AIDS researchers are beginning to admit, and the public is beginning to see (see above).
2

Genetica is the first scientific journal to offer an unprejudiced jury for AIDS research: a jury of scientific
researchers, who do not hold grants or companies studying mY, independent scholars, and investigative journalists.
It has moved AIDS research out of its 'Simi Yalley' to grant all views on AIDS a day in court for the public to see.
Two dozen scientists, scholars and investigative journalists accepted the opportunity to reappraise the status quo of
AIDS research. Most of them have questioned the mY-AIDS hypothesis before, but have since been censored, and
sociologically excluded from AIDS research, politics and journalism. Here they are united for the first time to put
on trial the mY-AIDS hypothesis. There are those who acquit my entirely, like Tom Bethell, David Causer, David
Chiu, Mark Craddock, Allen Downey, Bryan Ellison, Celia Farber, Neville Hodgkinson, Phil Johnson, Yladimir
Koliadin, John Lauritsen, Kary Mullis, John Papadimitriou, Eleni Papadopulos, Yal Turner, Malcolm Zaretsky
and myself. Others, including Peter Drotman, Harry Haverkos, Sheila Hobbs-DeWitt, Robert Root-Bernstein and
Gordon Stewart, make a case for my as a necessary but not sufficient cause of AIDS. Steven.B. Harris was the
only medical scientist who agreed to defend the hypothesis that my is sufficient to cause AIDS. Although he is
outnumbered, he covered a lot of ground as an advocate of the current AIDS establishment and as a prosecutor of
the heretics. The huge AIDS literature can serve as additional defense of the mY-AIDS hypothesis. Finally, there
are those who put AIDS science and journalism on trial, like Serge Lang, Harvey Bialy and myself.
The majority of articles in this volume reveal that the failing war on AIDS may be the most costly consequence
yet of our closed scientific system. The articles disclose the scientific, journalistic, and political biases that have
prematurely established and subsequently defended the entirely unproductive hypotheses that the AIDS epidemic
is infectious and that the retrovirus my is its cause.
The proceedings of this book show convincingly that, based on the free exchange of ideas, the scientific method
could very well find a solution of AIDS, but only if the my monopoly can be broken. This book illustrates that
the solution to AIDS could be as close as one of several very testable and very affordable alternatives to the
unproductive mY-AIDS hypothesis.

P.H. Duesberg
References

AIDS Weekly, 1995. Government Congressman questions funding for AIDS research. AIDS Weekly (electronic version) May, 22.
Benditt, J. & B. Jasny, 1993. AIDS the unanswered questions. Science 260: 1219,1253-1293.
Duesberg, P.H., 1992. AIDS acquired by drug consumption and other noncontagious risk factors. Phannacology & Therapeutics 55: 201-277.
Duesberg, P.H., 1994. Results fall short for mv theory. Insight, February 14, p 27-29.
Farber, C., 1995. AIDS-words from the front. SPIN, August, p 89.
Fields, B.N., 1994. AIDS: time to turn to basic science. Nature (London) 369: 95-96.
Swinbanks, D., 1994. AIDS chief promises a shift towards basic research. Nature (London) 370: 494.
P. H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 3-22, 1996. 3
© 1996 Kluwer Academic Publishers.

A critical analysis of the mv- T4-cell-AIDS hypothesis

Eleni Papadopulos-Eleopulos 1, Valendar F. Turner2, John M. Papadimitriou3, David Causer1,

Bruce Hedland-Thomas 1 & Barry AP. Pagel
1Department of Medical Physics, Royal Perth Hospital, Perth, Western Australia
2Department of Emergency Medicine, Royal Perth Hospital, Perth, Western Australia
3 Department of Pathology, University of Western Australia

Received 21 October 1993 Accepted 19 June 1994

Knowledge is one. Its division into subjects is a concession to human weakness.

Halford John Mackinder"
Abstract

The data generally accepted as proving the mv theory of AIDS, mv cytopathy, destruction of T4lymphocytes,
and the relationship between T4 cells, mv and the acquired immune deficiency clinical syndrome are critically
evaluated. It is concluded these data do not prove that mv preferentially destroys T 4 cells or has any cytopathic
effects, nor do they demonstrate that T4 cells are preferentially destroyed in AIDS patients, or that T 4 cell destruction
and mv are either necessary or sufficient prerequisites for the development of the clinical syndrome.

Introduction sidered proven by the data presently available. Refer-

With few exceptions by workers who either
reject it (Duesberg, 1987, 1992; Papadopulos-
Eleopulos, 1988; Papadopulos-Eleopulos etal., 1989a;
Papadopulos-Eleopulos, Turner & Papadimitriou,
1992a, 1993b), or who postulate the necessity for
cofactors (Lemaitre et al., 1990; Root-Bernstein,
1993), the currently accepted HIV theory of AIDS
pathogenesis states that:
1. HIV causes destruction of T4 (helper) lympho-
cytes, that is, acquired immune deficiency, AID;
2. AID leads to the appearance of Kaposi's sarcoma
(KS), Pneumocystis carinii pneumonia (PCP) and
certain other 'indicator' diseases which constitute
the clinical syndrome, S.
For this to constitute a valid theory of AIDS patho-
genesis the minimum requirements are:
1. HIV is both necessary and sufficient for destruction
ofT4-cells;
2. Decrease in T4 lymphocytes (AID) is both neces-
sary and sufficient for the appearance of the clinical
syndrome, S;
3. All AIDS patients are infected with mv.
Evidence will be presented which shows that the
HIVI AIDS hypothesis, as stated above, cannot be con-
ence will be made to an oxidative theory (Papadopulos-
Eleopulos, 1988; Papadopulos-Eleopulos, Turner &
Papadimitriou, 1992a, 1992b) which claims that the
immunological abnormalities seen in AIDS patients,
including decreased numbers of T4 lymphocytes as
well as the clinical syndrome, are induced by oxidis-
ing agents and not HIV.
Cytopathic effects of HIV
According to Gallo and his colleagues, 'HIV has been
shown to have a direct cytopathic effect' (cell killing
effect) on CD4+ cells, firstly by Montagnier and his
colleagues in 1983, and then by him (Gallo) and his
colleagues in a series of four papers published in Sci-
ence in 1984 (Shaw, Wong-Staal & Gallo, 1988). How-
ever, in the 1983 paper where Montagnier and his col-
leagues describe the isolation of HIV from a homo-
sexual patient with lymphadenopathy, no evidence
is presented regarding the biological effects of HIV
(Barre-Sinoussi et al., 1983). Although Gallo
claims that in the four Science papers (Gallo
et al., 1986) he and his colleagues 'provided clearcut
evidence that the aetiology of AIDS and ARC was
4
the new lymphotropic retrovirus, HTLV-III', no such
data were presented (Papadopulos-Eleopulos, Turner
& Papadirnitriou, 1993b). Reference to the cytopathic
effects is made only in the first paper where it was stat-
ed 'The virus positive cultures consistently showed a
high proportion of round giant cells containing numer-
ous nuclei (syncytia)' (Popovic, Sarngaharan & Read,
1984). The cultures described in that paper utilised
clones of the HT cell line; however, it subsequent-
ly became known that the HT line used by Gallo is
in fact HUn8 (Rubinstein, 1990), a cell line estab-
lished from a patient with mature T4-cell leukaemia
(Gazdar et at., 1980; Gallo, 1986). It has been shown,
however, that other cell lines established from patients
with mature T4-cell leukaemia have multinucleated
giant cells (Poiesz et at., 1980), and therefore one may
expect to find giant cells containing numerous nuclei
in the HT (clones) cell cultures even in the absence
of HIV. At present, evidence also exists showing
that other cells permissive for HIV, monocyte-derived
macrophages, 'in the absence of infection', form syn-
cytia during cultivation (Collman et at., 1989).
Later, Gallo expressed the view that syncytial for-
mation and direct cell killing are unlikely to be the
major pathway for cell loss. In addition, cells infected
by several viruses produce extensive syncytia without
cytopathy (Shaw, Wong-Staal & Gallo, 1988). In 1985,
Gallo and his colleagues (Gallo, Shaw & Markham,
1985) showed that in mitogenically stimulated lym-
phocyte cultures from AIDS patients or in cultures
from healthy donors 'infected' with HIV, there is a
decrease in the total number of viable cells. However:
(i) the decrease in viable cells begins before a signifi-
cant increase in reverse transcriptase activity (RT),
that is, HIV expression;
(ii) the rate of cell loss remains the same even when
the expression of HIV (RT), is maximum.
These suggest that the cause of the decrease
in viable cells may not be HIV. Since then other
researchers have shown that:
(a) 'lymphocytes may be productively infected in the
absence of cell death' (Hoxie et ai., 1985);
(b) the presence or absence of the cytopathic effects
is a function of the cell type (cell line), culture
conditions (presence or absence of interleukin-2
(IL-2), presence or absence of serum, fibrinogen,
fibronectin, alpha-globulin), and the origin of the
HIV preparation (von Briesen et at., 1987; Ushiji-
ma et at., 1992);
(c) early in 1986, Zagury, Gallo and their colleagues
reported that: 'T41ymphocytes from normal donors
infected by HTLV-III in vitro, as well as HTLV-III-
infected primary T4 cells from AIDS patients, have
been difficult to maintain in culture for longer than
2 weeks, and it has often been assumed that the
virus has a direct cytolytic effect on these cells'.
However, by avoiding PHA stimulation and by
reducing the number of cells per rnillilitre of cul-
ture medium from 105_106 to 103-104, they were
able to 'grow the infected cells for 50-60 days'
without cellular degeneration which, according to
them, was due to 'the lack of further antigenic
stimulation and, presumably, the reduced concen-
trations of toxic substances released by the mature
cells' (Zagury et at., 1986);
(d) cytopathy does not always correlate with RT activi-
ty, that is, HIV expression. 'In fact, there was some-
times an inverse correlation in CEM cells, with the
high RT isolates exhibiting a slower inhibition of
cell division and reduction of viability than the low
RT-producing viruses' (Cloyd & Moore, 1990).
In other words, the correlation between HIV pro-
duction and decreased cellular viability is not as the
HIV hypothesis predicts, especially if, as is presently
accepted, 'Although the effect of HIV on the immune
system resembles autoimmune disease, it is driven
by persistent, active, viral expression' (Weiss, 1993).
Despite all these data, consensus still prevails that HIV
infection leads to a 'quantitative decrease in the Twcell
population that will lead to acquired immune deficien-
cy syndrome (AIDS), (Ameisen & Capron, 1991) [TH
=T4]. However, no agreement exists as to the mecha-
nism by which HIV kills T4 cells.
According to Claude Ameisen and Andre Capron
from the Pasteur Institute, not one of the mechanisms
'proposed to account for these Twcell defects, includ-
ing: (1) immune suppression, or its opposite, hyperac-
tivation and exhaustion of the TH cells, (2) inhibitory
signals mediated by HIV viral or regulatory gene prod-
ucts, (3) autoimmune responses, (4) selective infection
and destruction of memory, TH cells, (5) syncytia for-
mation between infected and uninfected cells, and (6)
inappropriate immune killing of uninfected cells', is
satisfactory.
Instead, in 1991 they put forward the hypothesis
'that a single unique mechanism, activation-induced
T-cell death [also known as programmed cell death
(PCD) or apoptosis] can account for both the func-
tional and numerical abnormalities of T4 cells from
HIV-infected patients ... We propose that the simplest
explanation of Twcell defects leading to AIDS is that
HIV infection leads to an early priming of TH cells

for a suicide process upon further stimulation. In HIV
infected patients, circulating gp120, gp120-antibody
immune complexes or anti-CD4 autoantibodies, that
all bind CD4, may represent appropriate candidates
for the priming of T cells for a PCD response follow-
ing activation' (Ameisen & Capron, 1991). In support
of their theory they reported that stimulation of periph-
eral blood mononuclear cells (PBMC) of asymptomat-
ic HIV infected individuals with pokeweed mitogen
(PWM) or staphylococcal enterotoxin B (SEB), 'was
followed by cell death' , whereas no death was observed
at 48 h in the unstimulated cells. Cell death was only
observed in the CD4 + enriched population and not in
the CD8+ lymphocytes. Cell death was not found in
unstimulated or stimulated PBMC from HIV-negative
individuals (Groux et al., 1991, 1992). However, to
date, 'no evidence for circulating soluble gp 120 has yet
been reported' (Capon & Ward, 1991), or for gp120-
antibody immune complexes in AIDS patients. Fur-
thermore, although in the following years, researchers
from many institutions published data confirming the
apoptotic death of PBMC cultures from HIV infected
indi viduals, their data seem to contradict both Ameisen
and Capron's experimental findings as well as their
proposed mechanism of HIV induced apoptosis:
1. Addition of anti-gpl20 or anti-CD4 monoclonal
antibodies (MCA) to HlV infected cultures permit-
ted sustained high levels of viral replication, but
blocked apoptosis and cell cleath (Terai et al., 1991;
Laurent-Crawford et al., 1992);
2. Experiments performed on cultures with or without
stimulation showed 'both CD4+ and CD8+ cells
from HIV-infected individuals die as a result of
apoptosis' (Meyaard et al., 1992).
In a 1991 paper, published in Virology (Laurent-
Crawford et al., 1991), Montagnier and his colleagues
showed that:
(a) in acutely HlV infected CEM cultures in the pres-
ence of mycoplasma removal agent, cell death
(apoptosis) is maximum at 6-7 days post infec-
tion, 'whereas maximal virus production occurred
at Days 10-17' - that is, maximum effect pre-
cedes maximum cause;
(b) in chronically infected CEM cells and the mono-
cytic line, U937, no apoptosis was detected
although 'these cells produced continuously infec-
tious virus';
(c) in CD4 lymphocytes isolated from a normal donor,
stimulated with PHA and infected with HlV in the
presence of IL-2, apoptosis becomes detectable
3 days post infection and clearly apparent at 4
5
days. 'Intriguingly, on the 5th day' apoptosis
'became detectable in uninfected, PHA stimulat-
ed cells'. Figure 9, where the data are presented,
shows approximately the same degree of 'apoptotic
events' in the PHA cultures at 5 days as in the PHA
+ HIV cultures on the 4th day 'post infection' .
They concluded: 'These results demonstrate that
HIV infection of peripheral blood mononuclear cells
leads to apoptosis, a mechanism which might occur
also in the absence of infection due to mitogen treat-
ment of these cells ... Interestingly, HIV infection of
such mitogen stimulated cells resulted in a slight accel-
eration of the first signs of apoptosis, thus indicating the
intrinsic effect of HIV infection' (Laurent-Crawford et
al., 1991).
The conclusion that HIV has an 'intrinsic effect' on
PCD can be questioned on several grounds:
1. The 'slight acceleration of the first signs of apop-
tosis' in the stimulated HIV infected cultures, as
compared to the non-HIV infected stimulated cul-
tures, may not be due to HIV but to the many
non-HIV factors present in 'HIV' inOCUla, includ-
ing:
(a) Mycoplasmas and other infectious agents;
(b) The many cellular proteins present in the 'HIV
preparation' (Henderson et al., 1987);
(c) PHA, present in the cultures from which the
'HIV preparation' was derived;
2. That HIV is not the cause of apoptosis is also
indicated by the fact that in chronically infected
cell lines in which virus is continuously produced,
apoptosis is not detected;
3. That HIV may play no role in apoptosis is also
suggested by the presently accepted mechanism of
apoptosis. Apoptosis occurs both in healthy and
in pathological conditions, is frequently prominent
among the proliferating cells of lymphoid germi-
nal centres, and can be enhanced by numerous
agents including radiation, cytotoxic drugs, cor-
ticosteroids and the calcium ionophore A23187
(Kerr and Searle, 1972; Don et al., 1977; Wyllie et
al., 1980, 1984). Apoptosis is cellular death char-
acterised by morphological criteria: cellular con-
densation, DNA fragmentation, and plasma mem-
brane 'blebbing' leading to the release of 'apoptic
bodies' which vary widely in size and some of
which contain pyknotic chromatin surrounded by
intact membranes (Kerr & Searle, 1972; Don et al.,
1977; Wyllieetal., 1980, 1984). These changes are
thought to be induced by increased concentration of
Ca++ , which in its turn induces contraction of the
6
cytoskeleton whose main components are known to
be the ubiquitous proteins actin and myosin (Jewell
et ai., 1982; Cohen & Duke, 1984; McConkey et
ai., 1988, 1989; Reed, 1990).
However, evidence exists indicating that intracel-
lular Ca++ concentration and contraction of the actin-
myosin system (cellular condensation) are induced by
perturbances in the cellular redox state (Papadopulos-
Eleopulos et ai., 1985, 1989b). In fact, for more than
a decade, evidence has existed showing that oxidis-
ing agents, including all mitogenic (activating) agents,
can induce reversible cellular changes, cellular activa-
tion, malignant transformation, mitogen unresponsive
cells, or cellular death, including death by apoptosis.
The ultimate outcome depends on the concentration
of the agent, its rate of application, the initial state
of the cells and the cellular milieu (see Papadopulos-
Eleopulos, 1982).
More recent data confirm the fact that the intra-
cellular free Ca++ concentration is regulated by the
cellular redox state. Oxidation leads to an increased,
and reduction to a decreased, Ca++ concentration
(Trimm, Salama & Abramson, 1986). Cellular sur-
face blebbing (Jewell et ai., 1982; Lemasters et al.,
1987; Reed, 1990), chromatin condensation (Pelliccia-
ri et ai., 1983), and apoptosis (Morris, Hargreaves &
Duvall, 1984) are the direct result of cellular oxidation
in general and of cellular sulphydryl groups in partic-
ular. This is supported by Montagnier's group's recent
finding that apoptosis can be inhibited by reducing
agents (Ren6 et al., 1992). (In fact, at present, Mon-
tagnier (Gougeon & Montagnier, 1993) agrees with
our view that anti-oxidants should be used for treat-
ment of HIV/AIDS patients (Papadopulos-Eleopulos,
1988; Papadopulos-Eleopulos et ai., 1989a; Turner,
1990; Papadopulos-Eleopulos, Turner & Papadimitri-
ou, 1992a, 1992b)). At present it is also known that:
(a) for the expression of HIV phenomena (RT, virus-
like particles, antigen/antibody reactions), activa-
tion (mitogenic stimulation) is a necessary require-
ment (Klatzmann & Montagnier, 1986; Ameisen
& Capron, 1991; Papadopulos-Eleopulos, Turner
& Papadimitriou, 1992b);
(b) activation (stimulation) is induced by oxida-
tion (Papadopulos-Eleopulos, 1982; Papadopulos-
Eleopulos, Turner & Papadimitriou, 1992b);
Since both AIDS cultures and AIDS patients
are exposed to mitogens (activating agents), all of
which are oxidising agents (Papadopulos-Eleopulos,
1988), both apoptosis and the phenomena upon
which the presence of mv is based (viral-like parti-
cles, RT, antigen/antibody reactions (WB), 'HIV-PCR-
hybridisation') may all be the direct result of oxida-
tive stress and therefore their specificity may be ques-
tionable (Papadopulos-Eleopulos, 1988; Papadopulos-
Eleopulos, Turner & Papadimitriou, 1992a, 1992b).
As far back as January 1985 Montagnier wrote,
' ... replication and cytopathic effect of LAV can only
be observed in activated T4 cells. Indeed, LAV infec-
tion of resting T4 cells does not lead to viral repli-
cation or to expression of viral antigen on the cell
surface, while stimulation by lectins or antigens of
the same cells results in the production of viral par-
ticles, antigenic expression and the cytopathic effect'
(Klatzmann & Montagnier, 1986). One year later Gallo
and his colleagues wrote: 'the expression of HTLV-III
was always preceded by the initiation of interleukin-2
secretion, both of which occurred only when T-cells
were immunologically [PHA] activated. Thus, the
immunological stimulation that was required for IL-
2 secretion also induced viral expression, which led to
cell death' (Zagury et al., 1986). Thus, relatively early
after the appearance of AIDS it was known that HIV
is not sufficient for the appearance of the cytopathic
effects. For some unknown reason, up till 1991 very
little (or no) data were presented regarding the effects
of the activating agents themselves on cell survival.
However, in the 1991 Virology paper, discussed above,
Montagnier and his colleagues showed that activation,
in the absence of HIV, can induce the same cytopathic
effects. In other words, Montagnier and his colleagues
have shown that HIV is neither necessary nor sufficient
for the induction of the cytopathic effects observed in
HIV infected cultures. Thus, the presently available
evidence from the in vitro studies does not prove that
HIV has direct cytopathic effects on any T-cells, T4 or
T8. The cytopathic effects observed in the cultures are
most likely caused by the many activating (oxidising)
agents to which the cultures are exposed.
Even ifHIV were shown to have cytopathic effects,
since it is accepted that 'The hallmark of AIDS is
a selective depletion of CD4-bearing helper/inducer'
lymphocytes (Shaw, Wong-Staal & Gallo, 1988), the
available evidence must show that T4 cells are prefer-
entially destroyed in individuals at risk of developing
the clinical syndrome.
HIV and the T4 cells
Using MCA for serial measurement of CD4 and CD8
expressing lymphocytes in rnitogenically stimulated

HIV infected cultures, it has been shown that in cul-
tures prepared such that the majority (> 95%) of lym-
phocytes are purified T4 cells, there is a progressive
disappearance of CD4 expressing cells. This observa-
tion was interpreted by Gallo and others 'that H1LV-
III has a cytopathic effect on OKT4-positive (OKT4+)
cells' (Fisher et at., 1985). However, according to
Klatzmann, Montagnier and other French researchers
'this phenomenon could not be related to the cytopath-
ic effect' of HIV but is 'probably due to either modu-
lation of T4 molecules at the cell membrane or steric
hindrance of antibody -binding sites' (Klatzmann et at.,
1984(b); Klatzmann, Barre-Sinoussi et at., 1984(a».
That is, the decrease in T4 cells is not due to destruc-
tion of cells but due to a decrease in MCA binding to
their surface. Nevertheless, the above data were inter-
preted as evidence for selective infection and killing
of T4 cells by HIV, and together with the fact that
'we knew of no agents, aside from a family of human
T-Iymphotropic retroviruses that we had discovered
three years earlier and named human T-cell leukaemia
(lymphotropic) virus (H1LV), that demonstrated such
tropism to a subset of lymphocytes', was presented as
one of two arguments in support of the HIV hypothesis
of AIDS (Gallo, Shaw & Markham, 1985). (The other
argument was based on the perceptions that AIDS was
a new disease and the epidemiology was consistent
with an infectious cause).
However:
(a) HIV cultures/co-cultures are stimulated with such
oxidising agents as PHA, ConA, radiation, PMA,
polybrene and IL-2;
(b) these agents at relatively low concentration can
induce a decrease in CD4 expressing cells in the
absence of HIV (Acres et ai., 1986; Hoxie et ai.,
1986; Zagury et at., 1986; Scharff et ai., 1988)
without killing T4 cells.
(c) in 1986, Zagury, Gallo and their associates (Zagury
et at., 1986), prepared T-cell cultures (which con-
tained 34% CD4+ cells) from normal donors.
Cultures were stimulated with PHA and were (i)
'infected' with HIV; (ii) left uninfected. Control
cultures remained both unstimulated and uninfect-
ed. After 2 days of culture, the proportion of CD4 +
cells in the stimulated-uninfected and stimulated-
infected cultures was 28% and 30% respectively,
while at 6 days the number was 10% and 3%, the
controls not changing significantly.
Thus, HIV is not necessary for the disappearance
of CD4 expressing cells, as measured by the use of
MCA in 'HIV-infected' stimulated cultures. The stim-
7
ulants can induce the effect in the absence of 'HIV'.
Furthermore, the decrease in T4 cells may not be due to
destruction of T4 cells but to a decrease in the number
of cells binding MCA.
Even if the in vitro evidence shows that HIV is a
cytopathic retrovirus and that it preferentially infects
and kills T4 lymphocytes, evidence must exist that the
same effect takes place in vivo, that is, patients infected
with HIV have diminished numbers of T4 cells caused
by preferential infection and killing of these cells by
HIV.
Following the frequent diagnosis of KS, PCP and
other opportunistic infections (01) in gay men and
intravenous (IV) drug users, it was realised when T
lymphocytes of these patients were reacted with MCA
to the CD4 antigen, the number of CD4 antigen bearing
cells is diminished. This led to a diagnosis of 'acquired
immune deficiency' defined as a decrease in T4 cell
number, which was thought then and now to be due to
the death of T4 cells. This finding, together with the
then known fact that patients who were treated with
the so called immunosuppressive drugs or who suf-
fered from 'immunosuppressive illness' had relative-
ly high frequencies of KS and 01, led to the conclu-
sion that the high frequencies of these diseases in gay
men, IV users as well as haemophiliacs among others,
were the direct result of suppressed cellular immunity
(immunosuppression) defined by diminished numbers
of T4 helper cells (cell-mediated immunodeficiency).
In 1982, the Center for Disease Control (CDC) defined
a case of AIDS as 'illnesses in a person who 1) has
either biopsy-proven KS or biopsy-or culture-proven
life-threatening opportunistic infection, 2) is under age
60, and 3) has no history of either immunosuppres-
sive underlying illness or immunosuppressive therapy'
(CDC, 1982). The claim by Gallo and his colleagues
in 1984 that AIDS is caused by HIV led the CDC to
redefine AIDS. In 1985 the CDC defined AIDS as:
'I. one or more of the opportunistic diseases listed
below (diagnosed by methods considered reliable)
that are at least moderately indicative of underlying
cellular immunodeficiency; and
II. absence of all known underlying causes of cel-
lular immunodeficiency (other than LAV/H1LV-
III infection) and absence of all other causes of
reduced resistance reported to be associated with
at least one of those opportunistic diseases.
Despite having all the above, patients are excluded
as AIDS cases if they have negative result(s) on test-
ing for serum antibody to LAV/H1LV-III, do not have
a positive culture for LAVlH1LV-III, and have both a
8
normal or high number of T-helper (OKT4 or LEU3)
lymphocytes and a normal or high ratio of T-helper
to T-suppressor (OKT8 or LEU2) lymphocytes. In the
absence of test results, patients satisfying all other cri-
teria in this definition are included as cases' (WHO,
1986).
This definition presupposes that proof exists or can
be obtained that HIV is the sole cause of the acquired
immune deficiency (decreased T4) which, in turn,
leads to the appearance of the clinical syndrome. Such
a proof can only be obtained by the administration
of PURE HIV to healthy humans or, as Montagnier
(Vilmer et at., 1984) pointed out in 1984, 'Definite
evidence will require an animal model in which such
viruses could induce a disease similar to AIDS'. At
present no animal AIDS model exists and of course it
is not ethical to administer HIV, pure or otherwise, to
humans (Papadopulos-Eleopulos, Turner & Papadim-
itriou, 1993a). In the absence of the above one must,
at the very least, have (indirect) evidence that:
(a) in HIV positive indi viduals, at least by the time dis-
eases attributed to HIV infection such as persistent
generalised lymphadenopathy (POL) and AIDS-
related complex (ARC) have appeared, there is an
abnormally low T4 cell number;
(b) in patients defined as AIDS cases the decrease in T4
cells follows and does not precede 'HIV infection',
as evidenced by a positive HIV antibody test;
(c) patients before, during or after seroconversion have
not been exposed to any agents known to cause
immunosuppression;
(d) following seroconversion there must be a steady
decrease in T4 cell numbers.
However, three years after seroconversion the
majority of HIV positive individuals continue to have
normal T4 cell counts (Detels et at., 1988). Even in the
presence of POL and other 'constitutional symptoms of
HIV-related diseases', a significant number of patients
continue to have normal T4 cell numbers (T4!T8 ratio).
In some individuals, seroconversion is followed by an
increase, not a decrease in T4 cells (Detels et at., 1988;
Natoli et at., 1993).
When AIDS was first diagnosed in gay men and IV
drug users, but before the discovery of HIV, epidemio-
logical data, some of which appeared in the Morbidity
and Mortality Weekly Reports published by the CDC,
rapidly accumulated which showed that in the 1970s,
individuals from the AIDS risk groups suffered from
many infectious and non-infectious diseases unrelat-
ed to AIDS. Data was recently presented from the
Multicenter AIDS Cohort Study (Hoover et at., 1993)
(MACS) which shows that HIV seropositive gay men
'at least 1.67-3.67 years prior to a clinical diagno-
sis of AIDS', as well as HIV seronegative gay men,
although the frequency in the latter is lower, suffer
from a wide variety of complaints including fatigue,
shortness of breath, night sweats, rash, cough, diar-
rhoea, headaches, thrush, skin discolouration, fever,
weight loss, sore throat, depression, anaemia and sexu-
ally transmitted diseases. Evidence which existed at the
beginning of the AIDS era, or which has accumulated
since, shows that some of the diseases which occurred
in these individuals, or the agents which caused them,
including Epstein-Barr virus and CMV, are immuno-
suppressive (Papadopulos-Eleopulos, 1988). Many of
the agents used in treatment, including corticosteroids
and some antibiotics, as well as the recreational drugs
used by both gay men and drug users, are also known
to be immunosuppressive. From the start of the epi-
demic, the CDC was aware that approximately 50% of
gay men used nasal cocaine and about the same pro-
portion smoked marijuana. Nitrite use was considered
practically ubiquitous.
That the immunosuppression found in AIDS
patients is not caused by HIV is indicated by the fact
that individuals from the AIDS risk groups may have
low T4 cell numbers (T4!T8 ratio), even in the pres-
ence of a persistently negative HIV antibody test (Drew
et at., 1985; Novick et at., 1986; Donahoe et at.,
1987; Detels et at., 1988). Although one such study
showed 'reduced proliferative response to the T cell
mitogen PHA in AIDS ... PHA responses in symptom-
less HIV infection, with or without lymphadenopathy,
were also significantly reduced compared to hetero-
sexual controls. However, seronegative homosexuals
had similarly reduced PHA responses. Thus, in symp-
tomless infection, HIV does not appear to cause more
impairment than seen in their uninfected peers ... Our
findings re-emphasise the importance of using seroneg-
ative peer group controls in studies on HIV infection'
(Rogers, Forster & Pinching, 1989).
In considering the data from haemophiliacs, a
group of British researchers, including the well known
retrovirologist Robin Weiss, concluded in 1985: 'We
have thus been able to compare lymphocyte subset
data before and after infection with HTLV-III. It is
commonly assumed that the reduction in T-helper-cell
numbers is a result of the HTLV-III virus being trop-
ic for T-helper-cells. Our finding in this study that T-
helper-cell numbers and the helper/suppressor ratio did
not change after infection supports our previous con-
clusion that the abnormal T-Iymphocyte subsets are a

result of the intravenous infusion of factor VIII con-
centrates per se, not HlLV-III infection' (Ludlam et
at., 1985).
In relation to patients with haemophilia A, von
Willebrand's disease and 'hypertransfused patients
with sickle cell anaemia' Kessler et at. found that
'Repeated exposure to many blood products can be
associated with development of T4ff8 abnormali-
ties' including 'significantly reduced mean T4rr8 ratio
compared with age and sex-matched controls' (Kessler
et at., 1983). In 1984, Tsoukas et at. observed that
among a group of 33 asymptomatic haemophiliacs
receiving factor VIII concentrates, 66% were immun-
odeficient 'but only half were seropositive for HlLV-
III', while 'anti-HlLV-III antibodies were also found
in the asymptomatic subjects with normal immune
function'. They summarised their findings as follows:
'These data suggest that another factor (or factors)
instead of, or in addition to, exposure to HlLV-III is
required for the development of immune dysfunction
in haemophiliacs' (Tsoukas et at., 1984).
By 1986 researchers from the CDC concluded:
'Haemophiliacs with immune abnormalities may not
necessarily be infected with HlLV-IIIILAV, since fac-
tor concentrate itself may be immunosuppressive even
when produced from a population of donors not at risk
for AIDS' (Jason et at., 1986) (factor concentrate ==
factor VIII). In 1985 Montagnier (1985) wrote: 'This
[clinical AID] syndrome occurs in a minority of infect-
ed persons, who generally have in common a past of
antigenic stimulation and of immune depression before
LAV infection', that is, Montagnier recognised that in
the AIDS risk groups, AID appears before 'HIV infec-
tion' [LAV == HIV]. A recent study of IV drug users in
New York (Des Jarlais et at., 1993) showed that 'The
relative risk for seroconversion among subjects with
one or more CD4 count <500 cells/uL compared with
HIV-negative subjects with all counts> 500 cells/uL
was 4.53'. A similar study in Italy (Nicolosi et at.,
1990) showed that 'low number of T4 cells was the
highest risk factor for HIV infection', that is, decrease
in T4 cells is a risk factor for seroconversion and not
vice versa. The observations that T4 decrease precedes
a positive antibody test (,HIV infection'), is addition-
al (Papadopulos-Eleopulos, Turner & Papadimitriou,
1993a) evidence that factors other than HIV lead to
both T4 decrease and positive 'HIV' antibody tests.
Thus gay men, IV users and haemophiliacs, have
'known underlying causes of cellular immunodeficien-
cy (other than LAVlHlLV-III infection)', and there-
fore, according to the 1985 CDC AIDS definition, these
9
individuals cannot be AIDS cases. The finding in indi-
viduals belonging to the above groups of a decreased
T4 cells number and decreased T4/T8 ratio, even if
due to killing of T4 cells and not to 'modulation of T4
molecules at the cell membrane or steric hindrance of
antibody-binding sites', cannot be interpreted as being
caused by HIY. Nonetheless, from 1981 to the present,
gay men, IV users and haeomophiliacs form the vast
majority of AIDS cases.
From the beginning, it was realised that in AIDS
patients the decrease in T4 lymphocytes is accompa-
nied by an increase in T8 lymphocytes while the total
T cell population remains relatively constant. This has
recently been confirmed by Margolick et at., 1993 who
showed that the decline in T4 cells in HIV positive indi-
viduals is accompanied by a T8 increase 'with kinetics
that mirrored the loss of CD4 + cells, resulting in a
CD8 polarization' (Margolick et aI., Stanley & Fauci,
1993).
This finding has been neglected until recently when
a theory has been put forward to explain how infection
of even a small proportion ofT4 cells (perhaps 111000)
can have this effect. This theory states that 'loss of
either CD4 + or CD8+ cells is detected by the immune
system only as arlecrease in CD3+ T cells. The com-
pensatory response to such a selective decrease, then,
is to generate both CD4 + and CD8+ T cells in order
to bring the total CD3+ T cells back to a normal level.
The consequence of this nonselective T cell replace-
ment after a selective depletion of one T cell subset
would be an alteration in the CD4 to CD8 ratio after
normalization of the total T cell count with a polar-
ization toward the subset that had not been initially
depleted ... repeated events of selective CD4+ T-cell
killing will result in higher and higher CDS+ T-cell
count and lower and lower CD4+ T-cell count' (Adle-
man & Sofsy, 1993; Margolick et at., 1993; Stanley &
Fauci, 1993).
However, a brief look at the history of the discovery
ofthe T4 and T8 cells and the presently available data
show that the above theory may not be valid.
In 1974, a group of researchers from the National
Cancer Institute USA observed that when normallym-
phocytes were cultured with T-cells from hypogam-
maglobulinaemic patients in the presence of PWM,
the synthesis of immunoglobulin (antibodies) by the
normal lymphocytes was depressed by 84% to 100%.
They put forward the hypothesis 'that patients with
common variable hypogammaglobulinemia have cir-
culating suppressor T lymphocytes that inhibit B-
lymphocyte maturation and immunoglobulin synthe-
10
sis' (Waldman et al., 1974). Subsequently, it was
shown that ConA stimulated T cells from healthy ani-
mals 'can under appropriate circumstances perform
helper, suppressor, and killer functions' (Jardinski et
al., 1976). By 1977 many studies of the cellular basis
of the immune response had indicated that T cells have
both suppressive and helper activities and it was con-
cluded that 'these activities are specialized functions
of distinct subclasses ofT cells' , which could be distin-
guished by cell-surface components thought to be spe-
cific to each subclass (Cantor & Boyse, 1977). In the
late 1970s the discrimination and separation of these
two subclasses were facilitated by the development of
MCA to cell-surface antigens considered specific for
each subclass, the subclasses being given the name T4-
helper and T8-suppressor cells (Reinherz et al., 1979).
By 1980 it was generally accepted that:
(a) in humans the CD4 antigen and the CD8 anti-
gen are expressed on helper and suppressor T
cell subsets respectively. 'Each T-cell subclass
has a unique set of biological properties and
immunologic functions' (Cantor & Boyse, 1977).
'T4+ T cells provide helper function for opti-
mal development of cytotoxicity in cell-mediated
lympholysis ... In addition, the T4 + subset pro-
duces a variety of helper factors that induce B cells
to secrete immunoglobulin and all lymphocyte sub-
populations (T, B and null) to proliferate'. The
T8 subset 'suppresses the proliferative response of
other T cells and B-cell immunoglobulin produc-
tion and secretion' (Reinherz et al., 1981).
(b) cells of these two subclasses do not give rise to
one another. .. they represent products of separate
subclasses of thymus dependent maturation', that
is, 'although both T4+ and TS+ subsets arise from
a common progenitor cell within the thymus, they
di verge during ontogeny and result in separate sub-
sets' (TS :::::: T8).
(c) 'stimulation of T cells by conventional antigens,
histocompatibility antigens and mitogens results
in the formation of suppressor T cells' (Cantor &
Boyse, 1977; Reinherz et al., 1980, 1981).
The conclusions in (a) and (b) are at odds with evi-
dence published in the 1980s. In 1989 it was shown that
when 'monocytes adhered to plastic (but not when cul-
tured on Teflon), a significant decrease in CD4 expres-
sion was observed between 1 and 24 h post-adherence.
CD4 expression could not be detected in macrophages
adhered to plastic for S days by using four anti-CD4
monoclonal antibodies in flow cytometry or direct
immunofluorescence. Conversely, an increasing pro-
portion of adherent cells expressed LeuM3 and OKMS
surface antigens over the S days'. It was also shown
that:
(a) 'The down-regulation of CD4 was post-
translational' ;
(b) unlike monocytes cultured on Teflon, the adher-
ence of monocytes to plastic resulted in superoxide
anion generation, that is, oxidative stress (Kazazi
et al., 1989).
In the early 1980s, many researchers found that
under certain conditions, while the number ofT4 cells
decreases, the number of T8 cells increases and the
total number of cells remains constant or even increas-
es. In 1982 Birch et ai. showed that incubation of T
lymphocytes with adenosine or impromidine (an H2
histamine agonist) leads to a decrease in the number of
T-cells expressing the CD4 antigen and to an increase
in the number of T cells expressing the CD8 antigen
while the sum (T4 + T8) remains constant (Birch et ai.,
1982). In an experiment conducted in the same year by
Burns, Battye and Goldstein (1982), normal human
peripheral blood lymphocytes from different subjects
were grown in conditioned medium containing IL-2,
and, after varying periods of time in culture, the cells
were tested by indirect immunofluorescence for OKT4
and OKT8. The 'conditioned medium' (CM) consist-
ed of 'cell-free supernatant passed through a bacterial
filter' from 7-day cultures of PHA stimulated leuco-
cytes obtained from patients with hemochromatosis.
'For some experiments CM was freed of residual PHA
by passage over a tbyroglobulin-Sepharose column'.
They found that ' ... the cell population progressive-
ly increased in size to large blasts ... but most striking
was the rapid change in the OKT4 : OKT8 ratio of cell~
within the population, from 60: 40 to 40: 60 ... The
change in the surface phenotype of the major popula-
tion also occurred in cultures maintained in medium
containing IL2 which had been freed of PHA'. They
also found that the 'change in phenotype of the culture
as a whole took place very rapidly, often within one
day'; by 3 weeks the ratio OKT8: OKT4 was about
70: 30, and the 'change did not appear to be sim-
ply the preferential outgrowth of OKT8+ cells', but
a 'possible change in phenotype of cultured human
lymphoblasts, from OKT4 to OKT8' (Burns et al.,
1982). One year later in 1983, Zagury (an eminent
HIV researcher and Gallo collaborator) and his col-
leagues selected normal human T cells for in vitro
cloning according to the expression of T4, T8 or TIO
antigens on individual cells (Zagury et al., 1983). The
individual cells were cultured in the presence of TCGF

(IL-2) 'Preparations deprived of PHA', and 'an irra-
diated lymphoid cell filler-layer'. They summarised
their findings as follows: 'Clones were produced from
each of these cells irrespective of the antigenic phe-
notype of the parental cell. The cloned progeny man-
ifested, in many cases, shifts in antigen expression.
Thus, T4+T8- cells have clones expressing predomi-
nantly T4 - T8+ and vice versa. The clonal expression
of T4 and T8 seemed to be mutually exclusive. Anti-
genic shifts were recorded also in clones derived from
T4-T8-TlO- cells, resulting in TlO+ clones which
were also either T4+ or T8+ and from T4+T8-TlO+
cloned cells yielding clones of either T4 + or T8+ cells.
Testing functional properties we found that NK activity
was mediated not only by Tl 0+ cells but also, in some
cases, byT4+ andT8+ cells. Moreover, TCGFproduc-
tion, which may reflect helper activity, was mediated
not only by T4+ cells. Only the cytotoxic (CTL) activ-
ity seems to be confined to the T8 phenotype. Thus, it
appears that T antigens, which seemed to be molecular
markers of differentiation, are not markers for termi-
nal differentiation and do not always reflect defined
functional properties' (Zagury et at., 1983).
Given the in vitro evidence that:
(1) HIV is neither necessary nor sufficient for the
observed decrease in T4 cells numbers;
(2) T4 cells can change into T8 cells while the sum of
T4 + T8 remains constant;
(3) stimulation of T cells by PHA, ConA, radiation,
PMA and polybrene, all of which are oxidising
agents, leads to 'down regulation' of CD4 and
change ofT4 to T8; and the evidence that:
(i) individuals from the AIDS risk groups are
exposed to many oxidising agents including well
known mitogens;
(ii) in individuals at risk for developing AIDS the
decrease in T4 cell number is paralleled by an
increase in T8 cells (decrease in the T41T8 ratio),
while the total T cell number remains constant;
(iii) in individuals belonging to the main AIDS risk
groups the above changes can be observed in the
absence of HIV,
one must conclude that:
(a) the decrease in the T4 cell numbers and increase
in T8 cell numbers in 'HIV infected' cultures and
individuals is due to agents other than HIV; HIV
is neither necessary nor sufficient for the induction
of the above phenomenon;
(b) in vivo the above changes may not be due to a
selective destruction ofT4 cells and increased pro-
11
liferation ofT8 cells, but loss ofT4 surface markers
and acquisition of T8 surface markers.
T4 and the clinical syndrome
The HIV/AIDS researchers consider T4 decrease as
being the 'hallmark' and 'gold standard' of HIV infec-
tion and AIDS (Shaw, Wong-Staal & Gallo, 1988;
Levacher et at., 1992). In fact, in the most recent
(1992) CDC AIDS definition, an AIDS case can be
defined solely on serological (positive HIV antibody
test) and immunological (T4 cell count less than 200 x
1Q6!L) evidence (CDC, 1992). The new definition also
requires that 'the lowest accurate, but not necessari-
ly the most recent, CD4+ T-lymphocyte count should
be used' to define an AIDS case (CDC, 1992). How-
ever, ample evidence exists that T4 cell decrease can
be induced by many factors, some trivial, such as sun
bathing and solarium exposure, a decrease which can
persist for at least two weeks after exposure has ceased
(Hersey et at., 1983; Walker & Lilleyman, 1983). T4
cell counts 'can vary widely between labs or because
of a person's age, the time of day a measurement is
taken, and even whether the person smokes' (Cohen,
1992). That many factors can affect the T4 cell num-
ber is reflected by their large variation in HIV posi-
tive patients. In one such study, patient measurements
repeated by one laboratory within 3 days showed a
'minimum CD4+ cell count of 118 cells/mm3 and a
maximum CD4+ cell count of713 cell/mm3 ' (Malone
et at., 1990). In the MACS, consisting of 4954 'homo-
sexual/bisexual men', it was stressed that physicians
and patients should be 'aware that a measured CD4
cell count of 300 x 106!L really may mean it is like-
ly that the 'true' CD4 cell state is between 178 and
505 x 1Q6L. Thus there is no certainty this person's
'true CD4' is less than 500 x 1Q6!L or that it is greater
than 200 x 1Q6 L' (Hoover et at., 1992). It is impor-
tant to note that these variations were obtained despite
the fact that the CD4 measurements were undertaken
in laboratories which 'are carefully standardized in an
ongoing quality control program' .
In a study (Brettle et at., 1993) which examined
the impact of the 1993 CDC AIDS definition on the
annual number of AIDS cases as compared to the 1987
definition, it was found that if the definition was based
on:
(i) the 'first of two consecutive CD4 cell counts < or
equal to 200 x 1Q6!L', the number of AIDS cases
doubled;
12
(ii) one abnormal CD4 count, the number of AIDS
cases trebled.
Researchers at the University of California at Los
Angeles School of Medicine found that 5% of healthy
persons seeking life insurance had abnormal T4 cell
counts, and that 'In a subgroup of patients, the low
T-cell numbers or ratios appear to be stable findings'.
They concluded: 'In the absence of a history of a specif-
ic infection or illness or major abnormalities on a physi-
cal examination, it is not worthwhile to attempt to find a
specific cause for the abnormality of T-cell subsets ... A
uniform approach to this problem throughout the medi-
cal community will help alleviate patients' anxiety and
reduce the concern of the insurance industry about this
relatively common problem' (Rett et al., 1988).
If LAS , ARC, and the AIDS indicator diseases such
as KS and PCP are the consequence ofT4 cell depletion
then all groups of people who have a low T4 cell count,
irrespective of cause, should have high frequencies of
opportunistic infections and neoplasms. Conversely,
all patients with AIDS indicator diseases should have
abnormally low T4 cells.
In a study on the effects of blood transfusion on
patients with Thalassaemia major, researchers at the
Cornell University Medical Center and the Sloan-
Kettering Institute- for Cancer Research observed
decreased T4 cell numbers and inverted T4rr8 ratios
associated with the transfusions, but no increase in KS
or PCP, and concluded that ' ... studies which define
transfusion related AIDS on the basis of analyses with
monoclonal antibodies must be viewed with caution'
(Grady et al., 1985). Although patients with alcoholic
liver disease do not develop KS, PCP and other AIDS
indicator diseases more often than usual, they have
both immune deficiency and positive HIV antibody
tests leading researchers from the Veterans Admin-
istration Medical Centre to stress the importance of
recognising these facts: ' ... lest these patients be false-
ly labelled as having infection with the AIDS virus and
suffer the socioeconomic consequences of this diagno-
sis' (Mendenhall et aI., 1986).
Patients who have malaria have severe immunoreg-
ulatory disturbances including decrease in T cells. A
significant number of these patients also test positive
for HIV but they do not develop the AID clinical syn-
drome, leading Vol sky et al. to conclude, 'exposure to
HTLV-IIIILAV or the related retrovirus and the occur-
rence of severe immunoregulatory disturbances may
not be sufficient for the induction of AIDS' (Volsky et
al., 1986).
The MACS in the USA showed that 'even in the
absence of treatment, close to 25, 15 and 10% of men
were alive and asymptomatic 4,5 and 6 years after first
CD4+ < 200 x 106/L measurement' (Hoover, 1993).
In the same study comparing HIV positive individuals
who within five years progressed to AIDS (Group A)
with those who did not (Group B), it was found that:
'receptive anal intercourse both before and after sero-
conversion with different partners was reported more
frequently by men with AIDS. The ratio of the differ-
ences in this sexual activity between groups A and B
was higher at 12 (2.3) and 24 (2.6) months after sero-
conversion than before seroconversion (2.0)'. It was
concluded that 'sexually transmitted co-factors, pre-
seroconversion and/or postseroconversion ... augment
(or determine) the rate of progression to AIDS' (Phair
et al., 1992). However, since:
(a) sexually transmitted infectious agents are bi-
directionally transmitted, that is, from the active
to the passive partner and vice versa;
(b) in the above study the only sexual act directly relat-
ed to the progression to AIDS was passive anal
intercourse (unidirectionally);
one would have to conclude that the 'co-factors
that augment (or determine), progression to AIDS
are non-infectious. These findings are in agreement
with the oxidative theory of AIDS which claims
that both HIV phenomena (RT, virus-like particles,
antigen/antibody reactions, 'HIV-PCR') and AIDS
are caused by the many oxidative agents (includ-
ing semen), to which the AIDS risk groups are
exposed (Papadopulos-Eleopulos, 1988; Papadopulos-
Eleopulos et al., 1989a; Papadopulos-Eleopulos,
Turner & Papadimitriou, 1992a, 1992b) [PCR = poly-
merase chain reaction].
According to Canadian researchers, 'In TB as well
as in lepromatous leprosy, an immunosuppressive state
will frequently develop in the host. This state is char-
acterised by T lymphopenia with a decreased number
ofT helper cells and an inverted T-helper/T-suppressor
cell ratio ... immunosuppression induced by the infec-
tion with M. tuberculosis can persist for life, even
when TB is not progressive' (Lamoureux et al., 1987).
Yet these patients do not have high frequencies of KS,
PCP or other AIDS indicator diseases. In other words,
decrease in T4 cells is not sufficient for the AIDS indi-
cator diseases to appear. This is also supported by
evidence from animal studies. Experimental depletion
ofT4 cells in mice used as models for systemic Lupus
erythematosus in humans did not lead to increased fre-
quencies of neoplasms, nor did mice 'develop infec-

tious complications, even though they were housed
without special precautions'. In fact mice with low T4
cell numbers had 'prolonged life' (Wofsy & Seaman,
1985). It is also of interest that despite the indispens-
able role attributed to T4 and T8 lymphocytes in anti-
body production (helper and suppressor respectively),
AIDS patients, in the presence of low numbers of T4
cells and high numbers ofT8 cells, have increased lev-
els of serum gammaglobulins, and are not hypogam-
maglobulinaemic as might be expected. Also, although
human umbilical cord T-cells produce suppressor fac-
tor(s), the factor(s) is produced by T8- (T4+) notT8+
cells (Cheng & Delespesse, 1986). Thus, T4 and T8
cells do not seem to possess the generally accepted
functions attributed to them.
According to the HIV theory of AIDS pathogene-
sis, 'The Human Immunodeficiency Virus (HIV), the
etiologic agent of the acquired immunodeficiency syn-
drome (AIDS), has the capability of selectively infect-
ing and ultimately incapacitating the immune system
whose function is to protect the body against such
invaders. HIV-induced immunosuppression results in
a host defense defect that renders the body highly sus-
ceptible to 'opportunistic' infections and neoplasms'
(Fauci, 1988). Decrease of T4 cells to approximately
200 x 106/L leads to the development of 'constitu-
tional symptoms', and to less than 100 x 106/L to
'opportunistic diseases' (Pantaleo, Graziosi & Fauci,
1993). If this is the case then:
1. In all individuals with 'constitutional symptoms',
01 and neoplasms, the T4 cell number should be
abnormally low;
2. The decrease in T4 cells should precede the devel-
opment of the clinical symptoms since: (a) the
cause must precede the effect; (b) for many neo-
plastic and infectious diseases, there is evidence
that the diseases themselves and the agents used to
treat them may induce immune suppression includ-
ing decreased numbers of T4 lymphocytes and
reversal of T4/T8 ratios.
This is not the case even for the most serious and
characteristic of the AIDS diseases, KS and PCP.
In the MACS it was reported that:
(a) ' ... persistent generalised lymphadenopathy was
common but unrelated to immunodeficiency', and
'Although seropositive men had a significantly
higher mean number of involved node groups
than the seronegative men (5.7 compared with 4.5
nodes, p < 0.005), the numerical difference in the
means is not striking' .
13
(b) weight loss, diarrhoea, fatigue and fever, which
constitute the 'wasting' syndrome, (which at
present is an AIDS indicator disease), night sweats,
herpes zoster, herpes simplex (another AIDS indi-
cator disease), oral thrush, fungal skin infections
and haematological abnormalities were present
in both seronegative and seropositive individuals,
although some of them were present at higher fre-
quencies in the latter group. A relationship was
found between thrush, anaemia, fever and neu-
tropenia and T4 cell deficiency. However, 'the
clinical abnormalities were considerably better at
reflecting concurrent CD4 lymphocyte depression
than the low CD4lymphocyte counts were at deter-
mining clinical involvement' (Kaslow et al., 1987).
These observations are just as compatible with the
hypothesis that T4 lymphocyte deficiency is the
result and not the cause of the observed clinical
abnormalities.
KS, the main reason for which the retroviral
hypothesis was put forward, was initially postulated to
be caused by infection of normal cells with the retro-
virus. When, late in 1984 it became clear that the
KS cells were not infected with HIV, it was generally
accepted that the disease was caused by HIV indirect-
ly, that is, as a consequence of T4 cell decrease. At
present, it is generally believed that KS is caused by 'a
specific sexually transmitted etiologic agent' (Beral et
al., 1990; Weiss, 1993) other than HIV, but 'immune
suppression (both in AIDS and in transplant patients) is
the dominant cofactor for subsequent disease' (Weiss,
1993). However, unlike the United States CDC and
most AIDS centres around the world, for the Walter
Reed Army Institute of Research ' ... the presence of
opportunistic infections is a criterion for the diagno-
sis of AIDS, but the presence of Kaposi's sarcoma is
omitted because the cancer is not caused by immune
suppression ... ' (Redfield & Burke, 1988). In a study
by a group of researchers from Amsterdam regard-
ing the relationship between the T4 cell number and
the development of the clinical syndrome, KS was
excluded 'Because Kaposi's sarcoma may manifest at
higher CD4+ lymphocyte counts than other AIDS-
defining conditions' (Schellekens et al., 1992). This
is not surprising since by the beginning of the AIDS
era, the immune surveillance hypothesis of carcino-
genesis had been already refuted (Kinlen, 1982). In
fact, the presently available data indicate that KS in all
individuals, including gay men, may be caused by a
non-infectious agent (Papadopulos-Eleopulos, Turner
& Papadimitriou, 1992a). Even in the early stages
14
of the AIDS era, it was reported that KS in gay
men appeared following cQrticosteroid administration
(which was administered for diseases totally unrelated
to HIV or AIDS) and resolved when the drug was dis-
continued (Schulhafer et at., 1987; Gill et at., 1989).
Thus the HIVI AIDS hypothesis cannot account for the
very disease for which it was originally put forward.
In a study of 145 patients, 97% of whom were
homosexuals, with biopsy proven PCP at St. Vin-
cent's Hospital and Medical Centre, New York, 17%
of AIDS patients had a T4 cell count higher than
5001mm3 , and a further 14% between 301-500Imm3,
'in addition, patients with T4-T8 ratio greater than
1.0 and those with total T4 lymphocyte counts greater
than 500lmm3 did not show improved survival com-
pared with patients with abnormal values ... the degree
of suppression did not influence mortality' (Kales et
at., 1987). Researchers from the National Institute of
Allergy and Infectious Diseases and the National Can-
cer Institute studied 100 HIV-infected patients 'who
had 119 episodes of pulmonary dysfunction within
60 days after CD4 lymphocyte determinations'. T4
cells were less than 200 x 106/L before 46 of 49
episodes of PCP, 8 of 8 episodes of CMV pneumonia,
7 out of 7 Cryptococcat neoformans pneumonia, 19
of21 episodes of Mycobacterium avium-intracellutare
pneumonia, 6 of 8 [pulmonary] KS and in 30 out of 41
non-specific interstitial pneumonia. However, 'Before
the 119 episodes of pulmonary dysfunction were diag-
nosed in this study, the HIV-infected patients had man-
ifested the following clinical HIV-related disorders:
no disorders (4 episodes), Kaposi's sarcoma without
opportunistic infections (68 episodes), life-threatening
opportunistic infection (44 episodes), other AIDS-
related conditions (11 episodes)'. In addition, before
the diagnosis of the pulmonary episodes the patients
had received: 'zidovudine (36 episodes), interferon
(23 episodes), recombinant interleukin-2 (3 episodes),
cytotoxic chemotherapy (16 episodes), dideoxycyti-
dine (6 episodes), muramyl tripeptide (1 episode),
suramin (6 episodes), heteropolyanion 23 (5 episodes),
zidovudine plus interferon (5 episodes), nonablative
bone marrow transplantation (4 episodes). Twenty-two
episodes occurred in patients who had been receiving
neither experimental therapy nor zidovudine' (Masur
et at., 1989). These data may be interpreted as showing
that in some types of 'pulmonary dysfunction', most
cases (but not all) appear to be preceded by a CD4
count < 200 x 106/L. However, given the well known
fact that malignant neoplasms, infectious diseases and
the administration of chemotherapeutic agents may
themselves cause immunosuppression (Serrou, 1974;
Oxford, 1980; Reinherz et at., 1980; Rubin et at.,
1981; Thomas, 1981; Weigle, Sumaya & Montiel,
1983; Williams, Koster & Kilpatrick, 1983; Kempf &
Mitchell, 1985; Feldman et at., 1989), it is equally
plausible to argue that both 'pulmonary dysfunction'
and the low CD4 cell counts observed in patients were
the result of their recent past illnesses and previous
exposure to prescribed and illicit drugs and other fac-
tors.
In a recent study it was found that three patients who
developed PCP within 8-14 days of 'symptomatic, pri-
mary HIV infection' had normal T4 cell numbers and
T41T8 ratios 50-90 days before they became symp-
tomatic. During the symptomatic phase the T4 cell
count dropped to 62-91 cells/flL. However, 'With-
in four months of symptom onset, their CD4 counts
and CD4/CD8 ratios returned to normal'. In two of
the patients, a bisexual man and a gay man, 'HIV-
1 antibodies were detectable by EIA and WB' 30
days after these two individuals became symptomat-
ic (EIA == ELISA).
'Twenty-nine to forty-eight months after acquiring
HIV-l infection', all three patients still had normal
T4 cell numbers and were asymptomatic. The authors
concluded 'profound CD4lymphocytopeniacan revert
to normal without antiretroviral therapy' and stressed
'it is important that such cases are not misdiagnosed as
AIDS' (Vento et at., 1993).
That no relationship exists between 01 and T4
depletion was confirmed in a recent study where it
was shown that 'The appearance of 01 and wasting
syndrome was independent of T4 cells count' (Alejan-
dro et at., 1991), as well as other studies which show
that the OI may appear in the presence of normal T4
cell numbers (Stagno et at., 1980; Martinez, Domingo
& Marcos, 1991; Felix et at., 1992).
In conclusion, decrease in the number of T4 lym-
phocytes irrespective of how it is induced, that is, by
destruction of the T4 cells or by a phenotypic change,
and of its cause, is neither necessary nor sufficient for
the appearance of KS and OI including PCP, that is, of
the clinical syndrome.
HIV and AIDS
If HIV is either necessary and sufficient, or necessary
but not sufficient for the appearance of AIDS, then the
minimum requirement is that the virus be present in all
cases.

Three methods are used to demonstrate the pres-
ence of HIV: antibody tests, viral 'isolation', and PCR.
At present, 'the applications of PCR in the evaluation
of HIV-l seropositive individuals are not completely
defined' (Conway, 1990). Although PCR has a very
high sensitivity, the test is not standardised and its
reproducibility and specificity have not been deter-
mined. The limited data presently available suggest
that PCR is neither reproducible nor specific (Fox et
al., 1989; Conway, 1990; Dickover et al., 1990; Long,
Komminoth & Wolfe, 1992), even when the serologi-
cal status and not HIV, as should be the case, is used as a
gold standard (Defer, Agut & Garbarg-Chenon, 1992).
Furthermore, since the specificity of the primers used
in the PCR assay ultimately relates to the material orig-
inating from 'HIV isolates', the test specificity can be
no more meaningful (regarding the presence in AIDS
patients of an exogenous retrovirus), than 'HIV iso-
lation'. However, HN has never been isolated as an
independent particle separate!rom everything else. In
fact, by isolation is meant, at best, detection of two or
more of the following phenomena:
(a) reverse transcriptase, either in the cultures/co-
cultures or in material derived from these cul-
tures including nucleic acids and proteins, which
in sucrose density gradients bands at a density of
1.16 gmlml;
(b) proteins either in the cultures/co-cultures or band-
ing at 1.16 gmlml and which react with AIDS
patient sera;
(c) virus-like particles in the cultures.
Lately, for many researchers, including Montagnier
(Learmont et al., 1992; Henin et al., 1993), detection
in cultures/co-cultures of only p24 or reverse transcrip-
tion is considered synonymous with 'HIV isolation' .
The finding of the above phenomena cannot be
considered synonymous with 'HIV isolation'. They
can be used only for viral detection, and then if and
only if they have first been proven specific for the
virus. Not one of the above phenomena is specific to
HIV or even to retroviruses (Papadopulos-Eleopulos,
Turner & Papadimitriou, 1993a). Furthermore, and
most importantly, HIV cannot be isolated unless the
cultures are subjected to oxidative stress (mitogenic
stimulation, activation).
However:
1. The normal human genome contains many
copies of endogenous retroviral sequences (provirus-
es), 'including a complex family of HIV-l related
sequences' (Horwitz, Boyce-Janine & Faras, 1992),
a 'large fraction' of which 'may exist within a host
15
cell as defective genomic fragments. The process of
recombination, however, may allow for their expres-
sion as either particle or synthesis of a new protein(s)'
(Weiss et al., 1982; Varmus & Brown, 1989; Cohen,
1993; Lower & Lower, 1993; Minassian et al., 1993);
2. Cultivation of normal 'non-virus' producing
cells leads to retroviral production (expression); 'the
failure to isolate endogenous viruses from certain
species may reflect the limitations of in vitro coculti-
vation techniques' (Todaro, Beneviste & Sherr, 1976).
The expression can be accelerated and the yield
increased by exposing the cultures to mitogens, muta-
gens or carcinogens, co-cultivation techniques and cul-
tivation of cells with supernatant from non-virus pro-
ducing cultures (Toyoshima & Vogt, 1969; Aaronson,
Todaro & Scholnick, 1971; Hirsch, Phillips & Sol-
nick, 1972). For HIV isolation, in most instances,
all the above techniques are employed. Thus, even if
'true' (Popovic et al., 1984) retroviral isolation can be
achieved from the AIDS cultures/co-cultures, it would
be difficult if not impossible to be certain that the retro-
virus in question is an exogenous retrovirus. For such
evidence to be accepted as proof of the existence of
HIV, the activation of an endogenous provirus or a
provirus assembled by recombination of endogenous
retroviral and cellular sequences would need to be rig-
orouslyexcluded.
For example, in many cases of 'HIV isolation',
the human leukaemic cell lines CEM or HT(H9) are
co-cultured with tissue from AIDS patients which is
assumed to be 'infected with HIV' . The finding of two
or more of the following: (i) reverse transcription; (ii)
proteins which react with patient sera either in the co-
cultures or the material which bands at 1.16 gmlml; (iii)
retrovirus-like particles in the culture; is considered as
proof of the isolation from the patient of a retrovirus
(HIV) which infected the CEM or HT (H9) cells.
However, when CEM (CEM-SS) cells 'otherwise
negative for known human retrovirus', are stimulat-
ed with the mutagen ethyl-methyl-sulfonate (EMS),
'Large, syncytia-like cells reminiscent of those which
appear after a retrovirus infection were observed 5-
6 days after treatment. .. Cell-free supernatants from
CEM-SS cells heavily treated with EMS were able to
induce a transmissible retrovirus infection in Jurkat and
Molt 3 cells ... All attempts to identify viral expression
in the unmutagenized parental cells by EM, RT activ-
ity, or immunohistochemical methods were negative'
(Minassian et al., 1993) [EM = electron microscopy]. It
has already been stated that the HT cell line originated
from a patient with adult T4 cell leukaemia, a disease
16
which Gallo claims is caused by another retrovirus,
HTLV-1. If this is the case, CEM and HT (H9) cultures
would have retrovirus which, under the right condi-
tions, would be expressed even if the patient tissues
did not contain 'HIV'. Be this as it may, neither PCR
nor 'HIV isolation' have ever been used to demonstrate
a causal relationship between HIV and AIDS.
At present, as was the case in 1984, the claim that a
'causal relation between HIV and AIDS is compelling'
is based on the epidemiological relationships between
a positive 'HIV antibody' test and AIDS (Weiss, 1993).
One of these tests, the Western blot (WB), is consid-
ered to be both nearly 100% sensitive and specific,
and is used as a gold standard for the other tests.
Despite knowledge that cellular constituents and/or
fragments of the same buoyant density as retroviral
particles may contaminate the supernatants of cell cul-
tures (Papadopulos-Eleopulos, Turner & Papadimitri-
ou, 1993a), material for the WB is obtained by den-
sity gradient centrifugarion of the supernatant from
'HIV infected' cell cultures or even cell lysates,
the latter being the case in the first 'HIV isola-
tion' (Barre-Sanoussi et ai., 1983), and subsequent-
ly in other laboratories (Essex et ai., 1985; Albert
et at., 1988; Levinson & Denys, 1988). Material which
bands at 1.16 gmlml is considered to represent pure
HIV and consequently the proteins found at this densi-
ty are considered to be HIV antigens. For the Western
blot, these proteins are electrophoretically separated
according to molecular weight and charge. The sepa-
rated proteins are then transferred on to nitrocellulose
strips by electroblotting. When sera are added and the
strips developed, coloured bands appear representing
sites of protein/antibody reactions. Each band is des-
ignated by a small 'p' for protein, followed by its
molecular weight in thousands. Although the material
which bands at 1.16 gmlml is considered to represent
pure HIV, many of the proteins which band at this
density are accepted to be cellular proteins (Hender-
son et at., 1987), including proteins which react with
patient sera: 'Sera from some AIDS patients bound
a lot of cellular protein. In ELISA this problem was
overcome by comparing the serum binding to the viral
antigen with binding to a lysate of uninfected lym-
phocytes. This binding was apparent in the RIPA and
only sera which specifically precipitated the p25 [p24]
were regarded as positive' [RIPA =radioimmune pre-
cipitation assay] (Brun-Vezinet et ai., 1984; Burke,
1989). Even the proteins which are considered to be
HIV proteins may not be so (Papadopulos-Eleopulos,
Turner & Papadimitriou, 1983a, 1993b). For exam-
pIe, the p41 band which is considered by most AIDS
researchers as one of the most specific HIV proteins is
regarded by Montagnier' s group as being cellular actin
(Barre-Sinoussi et at., 1983). Furthermore, the pattern
of reaction, including that of the bands considered to
represent HIV proteins varies, from patient to patient
and in the same patient from time to time. Because of
this, criteria for the interpretation of the WB are nec-
essary. Yet, even today, ten years after the discovery of
HIV, there are no national USA or international agreed
criteria as to what constitutes a positive WB pattern.
Some institutions have more 'stringent' criteria than
others to define a positive WB. When the WB pattern
does not satisfy the definition for a positive test for
a given institution, but displays reactive bands, rep-
resenting either cellular or 'HIV proteins', the test is
considered to be indeterminate, (WBI). A WB which
has no reactive bands, representing either 'HIV' or
cellular proteins, is considered by all institutions as
negative (Lundberg, 1988).
For some time evidence has existed showing that:
(a) when the least 'stringent' criteria are used to
define a positive WB [p24 or p31132 and (p41
or pI20/160)], only approximately 80% of AIDS
patients test positive for HIV and this decreases
to less than 50% when the most 'stringent' [p24
and p31/32 and (p41 or pI20/160)] criteria are
used. The remaining AIDS patients have either
an indeterminate or a negative test (Lundberg,
1988). Conversely, according to the USA Con-
sortium for Retrovirus Serology Standardization,
127/1306 (10%) of sera from individuals at 'low
risk' of HIV infection, which 'includes specimens
from blood donor centers' have a positive WB even
when the most 'stringent' criteria are used to define
a positive test (Lundberg, 1988). (The Consortium
authors did not comment on the significance of the
occurrence of such stringently positive tests in low
risk individuals).
(b) WBI are very common in non-AIDS patients. For
example, 42% of patients transfused with HIV neg-
ati ve blood have WBI resul ts. In about 30% of these
patients, the WBI contains the p24 band, the band
considered by Montagnier's group to be the most
specific HIV band (Genesca et aI., 1989). (In fact
at present, for many researchers, the detection of
p24 in AIDS cultures/co-cultures is synonymous
with 'HIV isolation'). These results lead some
HIV researchers to conclude that 'WBI patterns are
exceedingly common in randomly selected donors
and recipients and such patterns do not correlate

with the presence of HN-l or the transmission of
HIV-l (Genesca et al., 1989).
(c) the specificity of an antibody test must be deter-
mined by the use of a gold standard. The only
valid gold standard for the HIV antibody tests is
HIV itself. However, to date, nowhere in the AIDS
scientific literature has there been any report what-
soever of the use of 'Human Immunodeficiency
Virus' itself as a gold standard for the verifica-
tion of the sensitivity and specificity of the HN
antibody tests. In fact, this may not be presently
possible since, even if one considers the phenom-
ena detected in AIDS cultures/co-cultures to be
HN and the methods used to represent unequiv-
ocal isolation, in the best laboratories, and with
no efforts spared, 'HIV can be isolated' only from
17-80% of HIV positive individuals (Chiodi et al.,
1988; Learmont et al., 1992). Since no gold stan-
dard has been used to confirm the specificity of
the WB results, the probability cannot be exclud-
ed that both WBI and WB results do not indicate
HIV infection and transmission, but are the result
of cross-reaction with antibodies directed against
non-HN antigens. This is especially the case in
AIDS patients and in individuals at risk of AIDS,
since both groups possess a vast array of antibod-
ies directed against many antigenic determinants
(Matsiota et al., 1987; Calabrese, 1988). Thus, a
positive 'HN antibody test' oughtto be regarded as
a non-specific marker for the development of AIDS
in the high AIDS risk groups, and should not be
regarded as a diagnostic and epidemiological tool
for HN infection (Papadopulos-Eleopulos, Turner
& Papadimitriou, 1993a). Notwithstanding, if:
(i) the sensitivity and specificity of the WB is nearly
100% as it is generally accepted;
(ii) only 50-80% (depending on which criteria are
used to define a positive WB) of AIDS patients test
positive;
then between 20-50% of AIDS patients are not infected
withmv.
Lately, some of the best known mv researchers
(Moore & Ho, 1992) have accepted that the clini-
cal syndrome, including its most specific and frequent
manifestation, KS and PCP, may appear in the absence
of HIV, that is, in patients in whom all HN tests includ-
ing the WB and PCR, are negative. For example, in
1991, Jacobs et al. (1991) reported that at the New
York Hospital-Cornell Medical Center during a three
month period, they diagnosed PCP in five adults. Two
out of three patients tested for T-Iymphocyte subsets
17
had T4 > 40% and all had normal T41T8 ratios. 'Cul-
tures of peripheral-blood mononuclear cells for retro-
virus were negative' in 415 patients, (the 5th apparently
was not tested). The HIV-l,2 antibody tests were neg-
ative in all cases. One year later workers from the
same institution and three other centres had 'identified
five other individuals from the New York City area
(four who have known risk factors for HIV infection),
with profound CD4 depletion and clinical syndromes
consistent with definitions of the acquired immunode-
ficiency syndrome (AIDS) or AIDS-related complex.
None had evidence of HN-l,2 infection, as judged
by multiple serologies over several years, standard
viral co-cultures for HN p24 Gag antigen, and provi-
ral DNA simplification by polymerase chain reaction'
(Laurence et ai., 1992). Similar cases have recent-
ly been reported from other institutions including the
CDC (Afrasiabi et ai., 1986; Pankhurst & Peakman,
1989; Safai et al., 1991; Seligmann et al., 1991; Siri-
anni et al., 1991; CDC, 1992; Hishida et al., 1992;
Tijhuis et al., 1993).
The available data do not support the presently
accepted hypothesis that mv is either necessary or
sufficient for the pathogenesis of AIDS, and thus it
would seem logical to consider alternative theories
(Papadopulos-Eleopulos, 1988; Duesberg, 1992).
Acknowledgements
We would like to thank all our colleagues and especial-
ly Richard Fox, Livio Mina, Garry James, Iris Peter, A.
Dufty, the staff of the Royal Perth Hospital Library and
the clerical staff of the Department of Medical Physics.
We also thank Harvey Bialy, Udo Schuklenk, Charles
Thomas, Gordon Stewart, Michael Verney Elliot and
Joan Shenton for continual encouragement, and Peter
Duesberg for inviting us to submit this paper to Genet-
ica.
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© 1996 Kluwer Academic Publishers.

Factor VIII, mv and AIDS in haemophiliacs: an analysis of their

relationship

Eleni Papadopulos-Eleopulos 1, Valendar F. Tumer2, John M. Papadimitriou3 & David Causer!

1Department of Medical Physics; 2Department of Emergency Medicine, Royal Perth Hospital. Perth, Western
Australia; 3 Department of Pathology; University of Western Australia

Received 17 February 1994 Accepted 14 June 1994

There are three steps in the revelation of any truth: in the first, it is ridiculed; in the second, it is resisted;
in the third, it is considered self-evident.
Arthur Schopenhauer
Abstract
In this review, the association between the Acquired Immune Deficiency Syndrome (AIDS) and haemophilia has
been carefully examined. especially the data that have been interpreted as indicating transmission of the human
immunodeficiency virus (mV) to the recipients of purportedly contaminated factor VIII preparations. In our view,
the published data do not prove the hypothesis that such transmission occurs, and therefore mv cannot account
for AIDS in haemophiliacs.

Introduction Factor vm and HIV

Currently, it is accepted that many patients with haemo-
philia have become HIV infected and/or developed the
AID clinical syndrome as a direct result of the transfu-
sion of factor VIII preparations contaminated with this
particular virus. That this is indeed the case requires
proof:
1. of the existence of a unique, infectious retro-
virus, HIV. (For a critical discussion of this issue
see Papadopulos-Eleopulos, 1988; Papadopulos-
Eleopulos, Turner & Papadimitriou, 1992; 1993a;
1993b);
2. of the existence of HIV in factor VIII preparations;
3. of the existence of mv in haemophiliacs;
4. that HIV is necessary and sufficient for the decrease
in T4 cells observed in haemophiliacs;
5. that HIV and a decrease in T4 lymphocytes are
necessary and sufficient for the development of the
clinical AID syndrome.
Since factor VIII is made from plasma, as a first step
in proving contamination of this blood product with
HIV, evidence must be presented that infectious viral
particles with morphological characteristics attributed
to HIV are present in the plasma of 'HIV infected'
individuals. Then it must be shown that HIV can sur-
vive (a) the time between blood collection and freez-
ing of plasma; (b) the freezing and thawing itself;
and (c) the process of manufacturing factor VIII from
thawed plasma. In other words, as Jay Levy succinctly
expressed in 1989, it is 'important to know whether
retroviruses could survive the preparation involved in
producing Factor VIII concentrates. Otherwise, AIDS
in many haemophiliacs [a minority may have other risk
factors] could not be explained' (Levy, 1989).
HN in plasma
To date,there is no evidence of the existence in human
plasma of particles with the morphological character-
istics attributed to HIV even though the plasma of
at least some 'HIV infected' individuals is claimed
to contain such particles. Thus Levy, whose team
24
reported most often on the relationship between HIV
and factor VIII wrote in 1988: 'Human Immunode-
ficiency virus in plasma or serum has been found in
about 30% of specimens from seropositive persons,
generally at a concentration of less than 10 IP/ml 12
[IP=infectious particles] (Levy, 1988). Reference 12
cited by Levy is a paper which he published in collab-
oration with Barbara Michaelis but this paper does not
contain a description of the method used to show that
(a) HIV seropositive (non-haemophiliac) plasma was
infected with 'HIV particles'; (b) HIV was 'present
in low titers' and (c) the particles were 'infectious'.
Commenting on this and his colleagues' findings Levy
wrote: 'These studies demonstrate further that not all
seropositive individuals have virus recoverable from
their PMCs and that isolation from serum is not a
common event' [PMCs=peripheral blood mononuclear
cells] (Michaelis & Levy, 1987). 'Thus, cell-free virus
in body fluids is unlikely to be a meaningful source
of HIV transmission' (Levy, 1988). At least one other
eminent HIVI AIDS researcher is also of the opinion
that HIV cannot be transmitted through ' ... products
prepared from blood, such as albumin, plasma, pro-
tein fractions, or hepatitis B vaccine' (Blattner, 1989).
If HIV cannot be transmitted through 'cell-free' body
fluids (plasma) because it is not found in the plasma
of 70% of seropositive individuals, and in the remain-
ing 30% is 'generally at a concentration of less than
10 IP/mI' , then it will be even less probable that factor
VIII prepared from plasma can be a 'meaningful source
of HIV transmission' since, even if HIV were present
in a plasma collection, it would be diluted many times
over during the process of factor VIII manufacture.
This is because factor VIII is made by pooling plasma
obtained from 2,000 to 30,000 individuals amongst
whom at most there will be only a few HIV seropos-
itives. Since factor VIII prepared from large batches
of pooled plasma is ultimately shared amongst many
haemophiliacs, the load of HIV for each haemophiliac
will be substantially lower than 10 IP/m\.
Since 1989, detection of a 24,000 molecular weight
protein (p24) in cell cultures (T cells from persons
presumed to be infected) or co-cultures (ofT cells from
persons presumed to be infected, with T cells from
normal individuals) has been used to quantify HIV
in cells, 'cellular viremia' (Masquelier et al., 1992).
Detection of p24 in cultures of T cells from normal
individuals with plasma from those presumed to be
infected has been used to quantify HIV in plasma,
'plasma viremia' (Coombs et al., 1989; Ho, Moudgil
& Alam, 1989; Clark et al., 1991). There are many
reasons why p24 cannot be used to quantitate or even
detect the presence of 'HIV infectious particles'. These
include:
(a) there is ample evidence that the p24 protein is not
HIV specific (Papadopulos-Eleopulos, Turner &
Papadimitriou, 1993a and see below);
(b) there is no relationship between plasma viraemia,
cellular viraemia (p24 in culture), and the titre of
p24 in (uncultured) plasma (HIV antigenaemia).
'Only 45 percent of patients with plasma viremia
had HIV p24 antigen in either serum or plasma'
(Coombes et al., 1989). 'Plasma p24-antigen titres
before or after acidification did not show any sig-
nificant correlation with quantification by tissue
culture method' (Weber & Ariyoshi, 1992). Nor
does correlation exist between the 'most specif-
ic' HIV antibody test, the Western blot (WB), and
plasma p24. With methods which have a report-
ed lower limit of sensitivity of 10-50 pglml, p24
can be detected in only 12% of HIV positive sera
(Jackson, Sannerid & Balfour, 1989);
(c) 'Much of the viral protein secreted from HIV-
infected cells is non-particulate, and the propor-
tion of (for example) p24 in virions is a function
of the viral genotype and the age of the culture. In
extreme cases, less than one percent of the total
p24 and gp120 present is in virions' (McKeating
& Moore, 1991). [It must be pointed out that in
the AIDS literature, the terms 'HIV', 'HIV isola-
tion', 'pure particles', 'virus particles', 'virions'
and 'infectious particles' have a variety of mean-
ings and include all of the following, but most
often without proof of the presence of a particle:
(i) 'RNA wrapped in protein'; (ii) material from
the cell culture supernatants which passes through
cell tight filters but through which organisms such
as mycoplasmas may pass; (iii) the pellet obtained
by simple ultracentrifugation of the culture super-
natant; (iv) recently, very often, detection in AIDS
cultures of p24 (Papadopulos-Eleopulos, Turner &
Papadimitriou, 1993a)].
In the process of preparing plasma for factor VIII
extractions, great care is taken to exclude cells. Even
if some cells are inadvertently present, it would be
most unlikely that they would constitute 'a meaningful
source of HIV transmission' since, like 'HIV particles',
'infected' cells present in the plasma of a seroposi-
tive donor would be diluted many times over by the
plasma and cells from the manifold number of non-
seropositive donors from which factor VIII is made.

Furthermore, according to some of the best known
HIV experts:
(a) 'in early and intermediate stages of disease' (it is
unlikely that individuals with advanced disease,
AIDS, would be able to donate blood), the fre-
quency of HIV infected cells in the blood as deter-
mined by the polymerase chain reaction (PCR) is
1110,000 in the early stages, and between 1110,000
and 111000 in the advanced stages (Pantaleo et al.,
1993);
(b) with the PRC one does not detect viral particles
or even the whole viral genome, but only a small
region, 'a gene at best' (Wain-Hobson, 1989);
(c) up to 99.9% of the 'HIV genomes' in the plasma
may be defective (Sheppard, Ascher & Krowka,
1993): that is, one or several genes are absent.
Plasma processing and HN
'Source plasma' obtained by plasmapheresis and fresh
frozen plasma from whole blood donation are best
suited for the preparation of factor VIII. The interval
between collection and freezing of plasma is approxi-
mately six hours (van Aken, 1991). The plasma is kept
frozen for lengthy periods, days to weeks, and is then
thawed for processing.
Researchers from the Laboratory of Molecular
Retrovirology, Georgetown University, took two blood
samples from each of the ten HIV seropositive patients:
'One sample from each individual was processed
immediately after phlebotomy to obtain plasma, and
aliquots of this plasma were used at once to infect
PHA-stimulated donor PBMCs as described. A sec-
ond set of aliquots of this 'immediately processed'
plasma was frozen at - 70° for 3 h, and then thawed
and used to infect the same donor cells. Five of the
ten immediately processed/immediately used plasma
samples (50%) were positive for HIV-1 using the p24
antigen detection method, while all of the correspond-
ing frozen aliquots were negative (0%). The second
blood samples from each of the 10 patients was kept
at room temperature for 3 h prior to plasma separation.
Again, after processing, one aliquot was used for the
infections while another was frozen and thawed before
use. In this experiment, only one of the ten samples
(10%) was culture positive after the 3 h delay and also
after the one cycle of freezing and thawing' (Dewar et
al., 1992). Thus, although these workers determined
the optimum conditions for 'HIV isolation' prior to
conducting the above experiments, they could 'iso-
late' (detect p24 culture) HIV from only 10% of HIV+
25
plasmas which were left at room temperature for three
hours and from 1 of 20 (5%) HIV+ plasmas which had
been frozen for three hours. In 1984, Levy himself,
using 'mouse retroviruses' reported that: 'The virus
titre (l08 IP) was not affected by mixing with cold
(5°C) plasma. In contrast, incubation of the virus with
plasma at 37°C for 30 min reduced its titre lOO-fold.
This finding accords with the report of complement-
mediated lysis of retrovirus by human serum' (Levy,
Mitra & Mozen, 1984). Other researchers have shown
'freeze-drying' parameters commonly employed under
commercial conditions for the preservation of protein
solutions are not favourable for survival of viral sus-
pensions' (Damjanovic, 1987). However, Levy and his
colleagues claim to have shown that a retrovirus 'can
survive and remain infectious after procedures used in
the preparation of factor VIII (FVIII), cryoprecipitate
or concentrates' . According to these researchers, when
HIV was 'added to human plasma (5°C), no reduction
in virus titre was observed'. Cryoprecipitate made from
the plasma contained 'a lO-fold reduced titre'. 'Purifi-
cation of cryoprecipitate by acid and glycine precip-
itation and filtration to achieve a sterile FVIII filtrate
resulted in a further 10-fold reduction in virus titre'.
Lyophilisationoffactor VIII filtrate 'lowered the infec-
tious virus titre about lO-fold. When this lyophilised
preparation was then heated, very low titre virus was
detectable after 10, 24 and 34 but not after 48 h of
heating' at 68°C. They concluded 'our results indi-
cate that lipid-enveloped retroviruses (both mouse and
human) if present in sufficient amount of plasma can be
found in infectious form in FVIII lyophilised products
... heating lyophilised FVIII for 72 h at 68°C or the
liquid product for 10 h at 60°C will eliminate infec-
tious ARV [HIV] if it is not present in the plasma at
more than 106 infectious particles/mi.' (Levy et al.,
1985). However:
1. Commenting on Levy and colleagues' findings
Damjanovic wrote: it is 'surprising that HIV sur-
vived procedures used in the preparation of Factor
VIII before lyophilization'.
2. Levy et al. performed their experiments by 'infect-
ing' plasma with 105 IP/ml, while factor VIII which
is administered to haemophiliacs is made from
plasma pooled from thousands of individuals most
of whom are not infected. Given that:
(a) the plasma from which factor VIII is prepared
contains very few or no particles per rn1 of
plasma;
(b) the technique employed to prepare factor VIII
reduced by a thousand fold the concentration
26
of any infectious particles present, even before
heat treatment; one would have to conclude that
factor VIII prepared before 1985 could not con-
tain sufficient HIV particles to be a 'meaningful
source of HIV transmission';
3. Levy and his colleagues detected and quantified
HIV particles 'by induction of reverse transcrip-
tase activity in the culture fluids of normal human
PMC maintained for up to 1 month after virus inoc-
ulation' (Levy et al., 1985). In Levy's laboratory,
PMCs were cultured with interleukin-2, polybrene
and phytohaemagglutinin (PHA). To prove HIV
infection, the activity of the enzyme reverse tran-
scriptase (RT) was determined using the primer-
template An.dT15 (Levy, Mitra & Mozen, 1984).
Detection of reverse transcription cannot be consid-
ered proof of the presence of a retrovirus, certainly
not HIV, and in fact, the above template-primers
can be copied by all cellular DNA polymerase (see
below). Because ofthis, reverse transcription ofthe
primer-template An.dT 15 cannot be used specifi-
cally to quantify or even detect HIV or any other
retrovirus.
HIV in factor V/Il
The belief, as Levy pointed out, that haemophiliacs
develop AIDS because they become infected with HIV
by receiving contaminated factor VIII can be enter-
tained if and only if evidence exists which proves that:
1. factor VIII used to treat haemophiliacs is contamin-
ated with HIV particles;
2. the particles are infectious.
A paper entitled 'Detection, quantification and
sequencing of HIV-l from the plasma of seropositive
individuals and from factor VIII concentrates' pub-
lished in 1991, is the only paper to claim proof of
the existence of HIV in factor VIII used therapeuti-
cally (Zhang et al., 1991). Using PCR the authors
tested eight batches of factor VIII, all 'unheated and
prepared before the introduction of donor screening
for anti-HIV antibodies'. Two batches 'gave positive
results; in one case with the env primers, the other
with the pol primers'. In sequencing their 'HIV RNA'
they found that the sequences were 'distinct from those
of all published HIV isolates and from any sequences
obtained previously in our laboratory'. Despite this,
they interpreted their signals as HIV and in fact quan-
tified the HIV and concluded: 'the calculated amount of
HIV RNA in both batches of reconstituted factor VIII
was only 2.5 copies per m!'. The minimum require-
ment for such an interpretation of a PCR signal (or
hybridisation in general), is prior proof that the PCR
primers and the hybridisation probes belong to a unique
retrovirus, HIV, and that the PCR and hybridisation
reactions are HIV specific. Detailed discussion of the
evidence has been presented elsewhere (Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993a) that the
specificity of the hybridisation signals in general and
of 'HIV' PCR in particular have not been determined,
and that the finding of viral RNA or DNA, even if
proven to belong to a unique retrovirus HIV, is not
proof of the presence of the viral particle. Some addi-
tional points are:
1. Most, if not all probes used for hybridisation
assays, including the PCR probes and primers,
are derived from the H9 (HUTI8) or CEM cell
lines. The H9 cell line originated from a patient
with T4 cell leukaemia, a disease which Gallo
claims is caused by a retrovirus similar to HIV,
HTLV-l (Gallo, 1986). In 1983 Gallo himself
reported that HUTI8 'contained HTLV proviral
sequences' (HTLV=HTLV-I) (Wong-Staal .et at.,
1983). Recently, a retrovirus has been 'isolat-
ed' from a non-HIV-infected CEM (SS) culture
(Minassian et at., 1993). Thus, the above cell lines
contain at least one retrovirus, if not more (see
below), even when not infected with HIV Since
even the well established method (Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993a) for
retroviral isolation (but which to date has never
been reported for HIV) cannot distinguish between
retroviruses, one cannot be confident that the 'HIV'
nucleic acid probes and PCR primers are indeed
specific for HIV;
2. The normal human genome contains HIV and
HTLV-l sequences (Parmentier et at., 1992;
Schneider et al., 1993);
3. The specificity for HIV of hybridisation assays
in general, and PCR in particular, can be deter-
mined only by the use of a gold standard. Howev-
er, according to one leading HIV/ AIDS researcher,
William Blattner, 'One difficulty in assaying the
specificity and sensitivity of human retroviruses
[including HIV] is the absence of a final "gold
standard'" (Blattner, 1989).
In addition to the above mentioned problems
there are many other difficulties associated
with the establishment of an HIV gold stan-
dard for PCRlhybridisation studies (Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993a). One
recently identified problem is the fact that there are

'striking differences' between the proviral DNA
and cDNA in one and the same PBMC sample
which 'could not be explained by either an arte-
fact of reverse transcriptase efficiency or template
selection bias' (Michael et al., 1993).
4. The presently available evidence obtained without
a gold standard suggests that the 'HIV hybridisa-
tion' is not HIV specific (Papadopulos-Eleopulos,
Turner & Papadimitriou, 1993a). Some additional
evidence:
(a) to address the question whether the neuronal
cells of patients with AIDS dementia com-
plex are infected with HIV, 'the brains from
10 patients with AIDS and neurological evi-
dence of viral encephalitis and the brains from
5 patients without HIV-l infection' were exam-
ined using an HIV gag probe. 'The antisense
riboprobe hybridized to cells known to be infect-
ed with HIV-l. It hybridised to HIV-l infected
A3.01 cells as well as splenic and renallympho-
cytes obtained at autopsies from patients known
to have AIDS. The probe did not, however,
hybridize to neurones in the brain sections from
10 patients with AIDS ... Surprisingly, when we
applied the control sense HIV-l gag probe to
the brain section from patients with AIDS, we
observed specific hybridization to neuronal cells.
Similarly, when brain sections from the five indi-
viduals not infected with HIV-l were examined,
the HIV-l sense probe detected transcripts in
neuronal cells. Our Northern blot analysis con-
firmed these results and demonstrated the pres-
ence of a 9.0-kb polyadenylated transcript in
brain tissues' (Wu et a!., 1993). Thus, either the
positive hybridisation signals obtained with the
antisense probe are non-HIV-specific or, as the
authors concluded, there is a neurone-specific
9.0-kb transcript that shows extensive homolo-
gy with antisense gag HIV-l sequences and that
this transcript is expressed in neuronal cells of
both HIV-l infected and noninfected individu-
als;
(b) the finding of positive PCR in eosinophils has
been interpreted to 'suggest that eosinophils
may act as host cells for HIV-l' (Conway
et at., 1992). However, 'Formaldehyde-fixed
eosinophils nonspecifically bind RNA probes
[HIV RNA] despite digestion with proteolyt-
ic enzymes and acetylation ... When prepara-
tions are treated with amounts of ribonuclease
27
adequate to destroy viral RNA, the eosinophilic
binding remains' (Natoli et at., 1993);
(c) negative controls and even buffers and reagents
may give positive HIV PCR signals (Conway,
1990);
One cannot but agree with Shoebridge et at. that 'until
further molecular biological and epidemiological stud-
ies are carried out, it will be unclear as to what detection
by PCR of proviral HIV-I DNA, even when shown to
be HIV-l, really means' (Shoebridge et at., 1991).
Infectious particles?
Even if it is proven beyond reasonable doubt that factor
VIII preparations contain HIV particles, the particles
could not be infectious. This fact is of such pivotal
significance it is essential to review the mechanism of
HIV infection as reported by leading HIV researchers.
According to:
1. Weber and Weiss, 'The first step in any viral infec-
tion is the binding of the virus particle to a com-
ponent of the host cell's membrane ... For some
time it has been known that the binding takes place
when CD4 interacts with an 'envelope' protein of
the virus called gp120' (Weber & Weiss, 1988);
2. Moore and Nara, 'HIV infection of CD4+ cells
is initiated by an interaction between its surface
glycoprotein, g120, and the cellular antigen CD4'
(Moore & Nara, 1991);
3. Mortimer, 'The gp120 surface protein interacts
with CD4 receptors on T4 cells so that the viral
RNA can be injected into the cell' (Mortimer,
1989);
4. Matthews and Bolognesi, 'First gp120 binds to
the CD4 receptor on an uninfected cell; then gp41
becomes anchored in the adjoining membrane; next
the two membranes begin to fuse, and the virus
spills its contents into the cell' (Matthews & Bolog-
nesi, 1988);
5. Redfield and Burke, 'Infection begins as a protein,
gp 120, on the viral envelope binds tightly to a pro-
tein known as the CD4 receptor on the cell surface'
(Redfield & Burke, 1988);
6. Rosenberg and Fauci, 'The initial event in the life
cycle of HIV is the high-affinity binding of the
HIV envelope glycoprotein (gp120) to CD4 that
is present on the surface of cells' (Rosenberg &
Fauci, 1990);
7. Montagnier et at., 'The gp120 is responsible for
binding the CD4 receptor' (Gougeon et at., 1993);
28
8. Haseltine and Wong-Staal, gp120 is 'crucial to
HIV's ability to infect new cells' (Haseltine &
Wong-Staal, 1988);
9. Callebaut et at., 'The human immunodeficiency
virus (HIV) infects lymphocytes, monocytes, and
macrophages by binding to its principal receptor,
the CD4 molecule, through the viral envelope gly-
coprotein gp120. The V3 loop of gp120 is critical
for HIV infection' (Callebaut et at., 1993).
Thus, there is general agreement that the HIV enve-
lope protein gp120 is crucial for HIV infection. How-
ever, agreement also exists that 'gp120 is easily shed
by virus and virus-infected cells' (Bolognesi, 1990).
Gelderblom and his colleagues at the Koch-Institute in
Berlin who have conducted the most detailed electron-
microscopy studies of 'HIV particles' have shown that
the knobs on the surface of the particles, where the
gp 120 is found, are only present in immature (budding)
particles, which are 'very rarely observed'. 'Mature',
cell-free particles do not have knobs, that is, gp120
(Hausmann et at., 1987).
Regarding infection by retroviruses, as far back as
1983 Gallo pointed out that 'the viral envelope which is
required for infectivity is very fragile. It tends to come
off when the virus buds from infected cells, thus ren-
dering the particles incapable of infecting new cells'.
Because of this Gallo said, 'cell-to-cell contact may be
required' for retroviral infection (Marx, 1983). Since
gp120 is 'crucial to HIV's ability to infect new cells',
and since gp 120 is not found in the cell free particles,
even if HIV particles are present in plasma or factor
VIII preparations, they will be non-infectious.
One must also consider the possibility that factor
VIII is contaminated with HIV-infected cells. Even if
the plasma from which the factor VIII is made contains
cells, since preparation of factor VIII entails (a) freez-
ing and thawing which lyses cells; (b) sterilisation by
filtration which excludes cells and the majority, if not
all, of cellular fragments from the filtrate; it is most
unlikely that factor VIII would be contaminated with
cells. Furthermore, even if the filtrate were to contain
some cellular fragments, they could not be a source of
HIV because the synthesis and assembly of type C and
type D particles, and Lentiviruses, require the presence
of an intact cell. In conclusion, the lack of evidence
of HIV particles in plasma, the use of non-specific
methods to detect HIV in cultures, the lack of gp120,
considered to be crucial for HIV infection in cell-free
particles and the physical processes involved in pro-
cessing plasma into factor VIII even before heating
was introduced, make it impossible for factor VIII to
be contaminated with infectious retroviruses. It is not
surprising, therefore, that to date nobody has reported
HIV particles in factor VIII preparations. Thus, on the
available evidence, HIV infected factor VIII cannot
be the explanation for AIDS in haemophiliacs. If fac-
tor VIII is not infected with HIV then it is mandatory
to explain the cause of the 'HIV-related' phenomena:
that is, positive antibody tests, HIV isolation, T4 cell
decrease and AIDS observed in haemophiliacs.
HIV antibodies in haemophilia
By 1988 most, if not all haemophiliacs, (in the USA,
Europe and Australia), were tested for HIV antibod-
ies and the vast majority of those tested were reported
as being positive. Based on the antibody tests, as far
back as 1984, the CDC concluded that 'These serolog-
ical data, indicating a high risk of exposure to LAV
from heavy users of factor VIII concentrates, support
the contention that LAV may be transmitted by some
blood products' (Ramsey et at., 1984). However, the
specificity of the HIV antibody test for HIV infection
have never been determined. According to Philip Mor-
timer, director of the Virus Reference Laboratory of
the Public Health Laboratory Service, London, UK:
'Diagnosis of HIV infection is based almost entire-
lyon detection of antibodies to HIV, but there can
be misleading cross-reactions between HIV-l antigens
and antibodies formed against other antigens, and these
may lead to false-positive reactions. Thus, it may be
impossible to relate an antibody response specifically
to HIV-J infection. In the presence of clinical and/or
epidemiological features of HIV-l infection there is
often little doubt, but anti-HIV-l may still be due to
infection with related retroviruses (e.g. HIV-2) which,
though also associated with AIDS, are different virus-
es' [italics ours] (Mortimer, 1989).
The specificity of an antibody test, any antibody
test, cannot be determined by 'clinical and/or epidemi-
ological features'. In the case of the HIV tests, this
practice may create several problems. Given the fact
that the vast majority of individuals who test positive
are asymptomatic, one must conclude that in these
individuals, a positive HIV antibody test is a false pos-
itive. Furthermore, the 1993 AIDS definition permits
the diagnosis of AIDS solely on the basis of a low
T4 cell count and positive HIV serology. It has been
estimated that the new AIDS definition will treble the
number of AIDS cases compared to the 1987 AIDS
definition (Brettle et al., 1993), most of whom may

be expected to be asymptomatic, and thus a significant
number of AIDS patients will have a false positive
HIV antibody test. Even if a patient did have one of
the AIDS 'indicator diseases' (none of which is new
and some of which are common), because:
(a) haemophiliacs are exposed to 'an array of alloanti-
gens (and infectious agents)' (Levine, 1985);
(b) gay men and intravenous users are also subjected
to a wide variety offoreign antigens and infectious
agents;
(c) all these groups are known to possess a plethora
of antibodies directed against numerous non-HIV
antigens;
one would expect cross-reactivity with 'HIV antigens'
to be the rule rather than the exception and thus, in
these groups, more than in any other, it will be difficult
to conclude that a positive HIV antibody test signifies
HIV infection and not cross-reactivity.
One cannot simultaneously use the presence of
AIDS as proof of HIV infection, and conversely, the
presence of a positive HIV test as proof that HIV is the
cause of AIDS, as presently is the case. The specificity
of an antibody test requires the use of the gold standard.
A gold standard is an alternative, independent method
of proving the presence or absence of the condition for
which the test is to be employed and in the case of
the HIV antibody tests the only admissible gold stan-
dard is HIV itself. However, the use of a gold standard
has never been reported and may not even be possi-
ble (Papadopulos-Eleopulos, Turner & Papadimitriou,
1993a). This is a view shared by William Blattner:
'One difficulty in assessing the specificity and sensi-
ti vity of retrovirus assays is the absence of a final 'gold
standard'. In the absence of gold standards for both
HTLV-l and HIV-l, the true sensitivity and specificity
for the detection of viral antibodies remain imprecise'
(Blattner, 1989). In fact, at present, there is ample
evidence which suggests that the HIV antibody tests,
even in the high AIDS risk group (gay men, IV drug
users, blacks and haemophiliacs), may not be specif-
ic (Papadopulos-Eleopulos, Turner & Papadimitriou,
1993a). Some additional data related to haemophilia
are:
(a) haemophilia patients have hypergarnmaglobuli-
naemia and hypergammaglobulinaemia correlates
with HIV seropositivity (Brenner et at., 1991);
(b) haemophilia patients have anti -lymphocyte anti-
bodies (Daniel, Schimpt & Opetz, 1989);
(c) in one study, 12% ofhaemophiliacs were found to
have HTLV-l antibody, (the molecular weights of
HTLV-l and HIV-l proteins are the same), 74%
29
anti-cardiolipin antibodies, 28% anti-nuclear anti-
bodies and 85% immune complexes (Matsudaet
at., 1993);
(d) HIV researchers accept that 'antilymphocyte,
antinuclear and other autoantibodies' give rise to
false positive HIV antibody tests (Biggar, 1986);
(e) in haemophiliacs, hepatitis B virus seropositivity is
a predictor for HIV seropositivity (Brenner et at.,
1991);
(f) at least one other group with chronic liver disease,
alcoholics, are known to have both false positive
antibody tests and immune deficiency (Mendenhall
et at., 1986).
As has been already noted by, 1988, most haemophil-
iacs had already been found to be HIV seropositive.
However, the test utilised by many researchers includ-
ing Gallo, Blattner, Weiss, Montagnier and Chermann
in papers published as late as 1990, was the ELISA
(Melby et at., 1984; Allain, 1986; Eyster et at., 1987;
Goedert et at., 1989; Wagner et at., 1990). Although
before 1988 some researchers used WB to confirm
the ELISA, the criteria used then to define a positive
WB would not satisfy even the 'least stringent' criteria
presently used to define a positive WB result (Lund-
berg, 1988). A few examples will suffice to illustrate
this point:
1. 'Serological reactions with any combination of
18 kd, 25 kd and 41 kd proteins of LAV were
scored as positive' (Jason et at., 1985);
2. 'A positive Western blot test was defined as the
presence of at least one band characteristic of anti-
body against an envelope protein (gp41, gp120, or
gp160) and at least one other HIV-l characteristic
band' (Jackson et at., 1988);
3. 'Serological reactions were scored as positive if
there was reactivity with the 41-kD protein of HIV
or reactivity with the 24-kD protein together with
anyone of several other HIV-associated proteins
(18 kD, 31 kD, 51 kD, 55 kD, 65 kD or 110 kD)'
(Lawrence et at., 1989).
Thus, it is a distinct possibility that if haemophili-
acs who have been tested using only ELISA, or even
ELISA and WB prior to 1988, were reappraised, a sig-
nificant proportion may no longer be classified as HIV
seropositive.
In 1984, a number of researchers from the USA,
including the well known retrovirologistMyron Essex,
reported the finding of HIV antibodies in haemophil-
iacs and concluded: 'The present results suggest that
exposure to HTVL-III is widespread in asymptomatic
haemophiliacs', but also added 'However, it is pos-
30
sible that a- significant proportion of asymptomatic
haemophiliacs might be exposed only to inactivated
HTLV-III rather than to the virus, owing to the manu-
facturing process involved in the preparation of com-
mercial factor VIII concentrate' (Kitchen et al., 1984).
But the mere fact that some HIV antibody positive
haemophiliacs have symptoms is not proof that they
are infected with the virus. (As we have already men-
tioned, one cannot simultaneously use the presence of
AIDS as proof of HIV infection, and conversely, the
presence of a positive HIV test <as proof that HIV is the
cause of AIDS).
Later, the finding that haemophiliacs who received
only heat treated factor VIII (van den Berg et aI., 1986;
CDC, 1987) also became HIV seropositive was inter-
preted as evidence that these patients 'may not have
been infected but rather immunized by preserved viral
proteins' (Damjanovic, 1989; Jackson, 1989). As far
back as 1985 researchers for the CDC wrote: 'It is
possible that antibody to LAV is acquired passively
from immunoglobulins found in factor VIII concen-
trates ., . Likewise, it is possible that seropositivity is
caused not by infectious virus but by immunization
with noninfectiousLAV or LAV proteins derived from
virus disrupted during the processing of plasma into
factor VIII concentrate' (Evatt et aI., 1985). Thus
a positive HIV antibody test cannot be considered
proof of HIV infection. Nonetheless, 'Because the
virus has been isolated from lymphocytes of about
3{)% of antibody-positive asymptomatic haemophili-
acs and because immune dysfunction has been pro-
gressive in other patients, it is believed that antibody
positivity is indicative of infection instead of immu-
nization in most, if not all, of the antibody-positive
haemophiliacs' (Bretter et al., 1988). According to
other authors, 'Strictly speaking, detection ofthe virus
is therefore necessary for diagnosis of an HIV infec-
tion in HIV-seropositive haemophiliacs' (Schneweis et
al., 1989). In conclusion, the presently available evi-
dence does not prove that a positive HIV antibody test
in haemophiliacs is proof of HIV infection.
Viral isolation
In a paper published in the Lancet in 1984 entitled
'Isolation of a New Lymphotropic Retrovirus from two
Siblings with Haemophilia B, one with AIDS', Mon-
tagnier and his associates were the first to describe
'isolation of HIV' from haemophiliacs. The T lympho-
cytes of the two children, one symptomatic and the oth-
er healthy, were cuJtured with, among other chemical
agents, PHA, IL-2; polybrene and anti-human alpha-
interferon. From the symptomatic sibling they reported
the following findings:
1. In the culture, retrovirus-like particles;
2. In the material from the cultures which in density
gradients banded at 1.16 gm/ml:
(a) proteins which using the ELISA reacted with
sera from a gay man with lymphadenopathy and
several specimens of the patient's serum collect-
ed prior to the blood used for 'HIV isolation'. No
serological data are given regarding the blood
from which the HIV was isolated. However,
the serum collected after treatment and clinical
improvement was non-reactive. In WB analysis
a p24/25 protein which banded at 1.16 gm/ml
was found to react with the patient sera as well
as with the serum from the gay man with lym-
phadenopathy. The same sera did not react with
goat antiserum specific for the p24/25 of HTLV-
I;
(b)RT activity which 'showed a preference for
poly-A-oligo-dT12-18 and poly-C-oligo-dG12-
18 overpoly-dA-oligo-dTI2-18, a feature which
usually distinguishes retroviral enzymes from
cellular DNA polymerases. The maximum activ-
ity was obtained with Mg2+ over Mn2+ with
poly-A-oligo-dT as template primer as previ-
ously described for human retroviruses such as
HTLV or LAV' . They also reported the finding
of 'viral' particles and RT in the culture from the
second sibling. In the ELISA his serum react-
ed with LAV and IDAV2 (immunodeficiency-
associated virus == the material from the culture
ofthe first patient which banded at 1.16 gm/ml).
In the WB, the p24 of IDAV2 was recognised
by his serum. Montagnier and his colleagues
concluded: 'Our findings are consistent with the
hypothesis that retroviruses such as that found in
our patients can be transmitted by way of plasma
products' (Vilmer et aI., 1984).
Using similar methods, researchers from the CDC and
the Children's Hospital of Los Angeles reported in
1985 the isolation ofHIV from 6 of 19 healthy seropos-
itive haemophiliacs (Gomberts et al., 1985). In 1987,
another group of American researchers reported the
isolation of HIV from 16 of 66 (24%) haemophiliacs
seropositive for HIV, but not from any of the six with-
out HIV antibody. For this, patients' PBMC were co-
cultured with cells from healthy seronegative donors
that had been stimulated with PHA. To the co-cultures

they also added IL-2 and polybrene. The findings in
the culture of:
(a)RT, 'An assay count of 104 cpm/ml (after sub-
traction of cellular polymerase activity) was con-
sidered positive for virus', using An.dT12-18 as
template-primer;
(b) cells positive for viral RNA by cytoplasmic dot
blot hybridisation;
were considered proof of HIV isolation (Andrews et
al., 1987).
Using the same co-culture techniques and condi-
tions as the above authors, in 1988 Jackson et al. test-
ed '75 unselected hemophiliacs to determine whether
patients positive for HIV-l antibody are actively infect-
ed rather than immunized by viral proteins in non-heat-
treated factor VIII or IX concentrates' . An 'ELISA kit
that primarily detects the core p24 antigen of HIV-l'
was used to test the culture. The finding of two serial
supernatant fluid samplings as positive, 'with the lat-
er sampling showing greater reactivity', was consid-
ered synonymous with HIV isolation. They reported
HIV isolation from '55 (98%) of 56' haemophiliacs
seropositive for HIV and concluded 'that antibody-
positive hemophiliacs have been actively infected by
mV-l' (Jackson et al., 1988).
In 1989 Schneweis et al. reported that between
1986 and 1988 they were able to 'isolate HIV' from 70
of 211 (33%) of haemophiliacs who were seropositive
for HIV. 'After March 1988 an increase in sensitivity of
virus isolation was attained by testing the supernatants
of the culture for the presence of p24 antigen (p24Ag)
instead of reverse transciptase (RT)' (Schneweis et al.,
1989). One year later the same authors 'isolated' HIV
from 29 of 46 haemophiliacs (63%) (Wagner et al.,
1990). As can be seen, by HIV isolation is meant
detection of one or more of the following phenome-
na: rarely, virus-like particles and positive hybridisa-
tion signals for 'viral' RNA, and most often RT and
p24. Elsewhere we have presented evidence that detec-
tion of these phenomena cannot be considered synony-
mous with isolation. They can only be used for viral
detection, and even then if, and only if, they are first
shown to be specific for HIY. The above phenomena
have been discussed in detail (Papadopulos-Eleopulos,
Turner & Papadimitriou, 1993a) and it has been shown
that none is specific for HIV or even for retrovirus-
es. Below some additional points regarding virus-like
particles, RT and p24 will be considered, (addition-
al points regarding hybridisation have been presented
above).
31
Virus-like particles
Although the origin and role of 'retrovirus particles'
are not known, they are considered ubiquitous and this
is especially the case in cell cultures and in patholog-
ical tissue. In 1969/Chopra and Feller, noticing that
'Virus like particles resembling the C-type [some clas-
sify HIV as a C-type] particles associated with mouse
leukemia have been reported in human leukemic tis-
sues by a number of investigators' reported that: 'These
particles have been observed in the density gradient
purified fractions of milk samples obtained from wom-
en having breast cancer and from milk of a normal
woman with a family history of breast cancer. A few
particles have also been detected in tissue-culture of a
breast cancer biopsy' (Chopra & Feller, 1969). Levine
et al. examined (blindly) plasma of leukaemic and
healthy individuals: 'A specimen was considered pos-
itive if there were numerous double-membraned par-
ticles with dense nucleoid which were about 100uu
in diameter and comparable to the type C particles
described by Porter and Dalton. A specimen was des-
ignated as suspicious if particles were found which
were morphologically similar to those in positive spec-
imens, but were very few in numbers. Specimens with
numerous but less typical particles and 'empty' parti-
cles were also considered suspicious. All other spec-
imens were classified as negative ... In this study the
problems of false positives was largely eliminated by
using ultrathin sections of high speed plasma pellets'.
They reported that 'Of 45 patients with myelocytic
leukemia, five with acute and four with chronic mye-
locytic leukemia showed multiple virus-like particles.
Seven additional patients had similar particles in less-
er numbers or particles devoid of the dense nucleoid.
In these 16 patients the particles were detected when
the disease was untreated or not responding to thera-
py. Three patients with acute myelocytic leukemia and
numerous virus-like particles in the florid leukemic
phase showed no particles while in complete or par-
tial remission. Numerous particles were found in the
plasma of one patient with acute lymphocytic leukemia
but were not found in samples from 14 patients with
chronic lymphocytic leukemia. One suspicious sample
was obtained from a patient with infectious mononu-
cleosis but 14 other nonleukemic samples were neg-
ative' (Levine et al., 1967). In 1972, virus-like parti-
cles with morphological characteristics similar to those
ascribed to HIV by some researchers (Lentiviruses)
were reported in cultures of human brain cells (Hooks
et al., 1972). By 1974, researchers from the Koch-
32
Institute in Germany, including Gelderblom, report-
ed virus-like particles in HeLa cells, and Canadian
researchers reported the same particles in cultures of
marrow cells from leukaemic patients (Bauer et al.,
1974; Mak et al., 1974; Watson et al., 1974). In con-
clusion, particles with morphological characteristics
ascribed to HIV are not specific to this virus.
Reverse transcriptase
Although at present some of the best known AIDS
researchers consider RT as being the 'sine qua non' of
retroviruses, and regard the detection of reverse tran-
scription in lymphocyte cultures from AIDS patients
not only as proof of the presence of such viruses but of
HIV itself, according to some of the best known retro-
virologists, including the discoverers of RT, reverse
transcription is a property of all cells, and is by no
means confined to retroviruses (Temin & Baltimore,
1972; Varmus, 1987).
'Reverse transcriptase (RT) was first discovered as
an essential catalyst in the biological cycle of retro-
viruses. However, in the past years, evidence has accu-
mulated showing that RTs are invol ved in a surprisingly
large number of RNA-mediated transcriptional events
that include both viral and non viral genetic entities
... the possibility that reverse transcription first took
place in the early Archean' is supported by a number
of facts and 'the hypothesis that RNA preceded DNA
as cellular genetic material' (Lazcano et al., 1992).
As has already been stated, when the HIV
researchers Andrews and colleagues used RT for prov-
ing HIV isolation from haemophiliacs 'An assay count
of 104 cpm/mL (after subtraction of cellular poly-
merase activity) was considered positive for virus'.
However, the demonstration of higher levels of reverse
transcription from the cells of haemophiliacs is not
proof that the activity is due to HIV. How does one
know that the higher activity of these cells is not due
to:
(a) activation 'of cellular polymerase activity' by fac-
tor VIII itself or the many contaminants present
in factor VIII preparations to which haemophiliacs
are exposed?
(b) the many factors (PHA,IL-2, polybrene) to which
the haemophiliacs' cultures are exposed?
Even ifRTwere a property only of viruses, it is notspe-
cific to retroviruses. According to Varmus: 'Reverse
transcription was assigned a central role in the replica-
tion of other viruses [hepatitis B and cauliflower mosa-
ic viruses] and in the transposition and generation of
other kinds of eukaryotic DNA' (Varmus, 1988). 'The
hepatitis B viruses (HBVs) are small DNA viruses that
produce persistent hepatic infections in a variety of ani-
mal hosts and replicate their DNA genomes via reverse
transcription of an RNA intermediate. All members of
this family contain an open reading frame (ORF), 'P'
(for pol), which is homologous to retroviral pol genes'
[pol=polymerase] (Chang et al., 1989). 'Hepatitis B
virus (HBV) resembles retroviruses, including HIV,
in several respects. In particular, both viruses contain
reverse transcriptase, and replicate through and RNA
intermediate'. Because of this, it has been suggest-
ed that hepatitis B infection should be treated with
the same antiretroviral agents as HIV infection (Mit-
suya & Broder, 1989). At present, evidence exists
which shows that although the major target organ for
hepatitis B virus is the liver, cells other than hepa-
tocytes 'including peripheral blood lymphocytes and
monocytes, may become infected with HBV' (Neu-
rath, Strick & Sproul, 1992). Lymphocyte stimula-
tion in general and PHA stimulation in particular is
associated with production of hepatitis B virus from
peripheral blood lymphocytes in patients infected with
HBV including 'viral replication in chronic hepatitis B
infection of childhood' (Vegnente et aI., 1991; Sarria
et al., 1993). It is of pivotal significance to note that
98% ofHIV seropositive patients with haemophilia are
infected with hepatitis B virus (Brenner et al., 1991).
It is also of interest to note that AIDS patients suffer
frequently from bacterial infections and that 'bacteria
too, have reverse transcriptases' (Varmus, 1989).
In 1989 Blattner wrote: 'Assays for reverse tran-
scriptase, the unique viral enzyme, employ special
oligonucleotide templates in the presence of magne-
sium. A characteristic profile of enzyme activity sug-
gests the presence of a retrovirus, but false positivity
arising from cellular enzyme activity or false negativi-
ty because of low reverse transcriptase level make this
technique too unreliable for epidemiologic application'
(Blattner, 1989).
However, there is no 'characteristic profile of
enzyme activity' in haemophilia cultures/co-cultures
and no 'special oligonucleotide templates' are used. To
prove HIV infection, all researchers use the template-
primer poly-A-oligo-dTl2-18 (An.dT 1s ). However,
this template-primer is not specific to retroviral RTs. As
far back as 1972 Gallo and his colleagues showed that
reverse transcription of the template-primer An.dTls
can be achieved with material obtained from cultures of
'PHA stimulated (but not unstimulated) normal human
blood lymphocytes', which in sucrose density gradi-

ents bands at 1.16 gmlml (Gallo, Sarin & Wu, 1973).
Not only is this template-primer not specific to retrovi-
ral RT, but all the cellular DNA polymerases, 0:, (3 and
" can copy An.dTls (Sarngadharan, Robert-Guroff &
Gallo, 1978). In fact, in 1975, an International Con-
ference on Eukaryotic DNA polymerase (Weissbach et
at., 1975) defined DNA polymerase " 'a component
of normal cells' (Robert-Guroff et at., 1977) 'found to
be widespread in occurrence' (Sarngadharan, Robert-
Guroff & Gallo, 1978), whose acti vity can be increased
by many factors, including PHA stimulation (Lewis et
at., 1974), as:
the enzyme which 'copies An.dT1s with high efficien-
cy but does not copy DNA well' (Weissbach et at.,
1975). Thus, reverse transcription, including that of the
primer-template An.dTlS, cannot be considered specif-
ic to HIV or even to retroviruses.
The p24 protein
The p24 protein is considered to be coded by the HIV
gag gene, that is, by the gene which codes the group
specific antigens of retroviruses. As far back as 1974
Gelderblom and his colleagues wrote 'While the virus
envelope antigens are primarily virus-strain specific,
the bulk of internal proteins of the virion with molec-
ular weight (mw) between 10,000 d and 30,000 d are
group-specific (gs) for viruses originating in a giv-
en animal species (gs-spec. antigens). The major pro-
tein constituent of mammalian C-type oncornaviruses
with a molecular weight in the range of 30,000 d was
found to possess, besides gs spec. antigen, an antigenic
determinant that is shared by C-type viruses of many
mammalian species including monkeys and was thus
termed gs interspecies (gs-interspec.) antigen' (Bauer
etat., 1974). As late as 1983 Blattner stated: 'It may be
feasible to use viral antigen probes to look for cross-
reactive antibodies, since certain viral proteins, partic-
ularly the polymerase and gag proteins, may be highly
conserved between subtypes of virus' (Blattner, 1989).
Thus, even if p24 were to be specific to retroviruses,
it cannot be HIV specific. Indeed, apart from a joint
publication with Montagnier in 1988 (Gallo & Mon-
tagnier, 1988) where it is claimed that p24 is unique to
HlV, Gallo and his colleagues have repeatedly stated
that the p24 of HIV and of two other human retro-
viruses, HTLV-l and HTLV-II, which Gallo claims to
have isolated from humans, immunologically cross-
react (Wong-Staal & Gallo, 1985).
The whole blood cultures of 49/60 (82%) of 'pre-
sumably uninfected but serologically indeterminant
33
individuals and 5/5 seronegative blood donors' were
found positive for p24 (Schupbach et at., 1992). The
'HIV proteins (pl7, p24)' appear in the blood of
patients (previously negative for all HIV markers) fol-
lowing 'transfusions of HIV-negative blood and UV-
irradiation of the autoblood' (Kozhemiakin & Bon-
darenko, 1992). p24 is detected in a significant num-
ber (up to 36% of patients with systemic lupus ery-
thematosus) (Barthel & Wallace, 1993). Detection of
p24 has been also reported in organ transplant recipi-
ents. In one kidney recipient (the donor was negative
for p24 antigen) who, three days following transplan-
tation developed fever, weakness, myalgias, cough
and diarrhoea, all 'Bacteriological, parasitological and
virological samples remained negative [including HIV
PCR]. The only positive result was antigenaemia p24,
positive with Abbot antigen kits in very high titers of
1000 pg/ml for polyclonal and 41 pg/ml for mono-
clonal assays. This antigenaemia was totally neutraliz-
able with Abbot antiserum anti-p24 ... 2 months after
transplantation, all assays for p24-antigen became neg-
ative, without appearances of antibodies against HIY.
Five months after transplantation our patient remains
asymptomatic, renal function is excellent, p24 antige-
naemia still negative and HIV antibodies still nega-
tive' (Vincent et at., 1993). Using two kits, the Abbot
and Diagnostic Pasteur, in one study p24 was detect-
ed transiently in 12114 kidney recipients. Peak titres
ranged from 850 to 200000 pg/ml 7-27 days post-
transplantation. Two heart and 517 bone marrow recip-
ients were also positive, although the titres were lower
and ranged from 140-750 pg/ml. Disappearance of p24
took longer in kidney (approximately 6 months) than
in bone-marrow (approximately 4-6 weeks) recipients.
According to the authors: 'This may be related to dif-
ferences in immunosuppression therapy.' Discussing
their findings they wrote: 'The observation of a 25-
30 kD protein [the French researchers report p24 as
p25] binding to polyclonal anti-HIV human sera after
immunoblots with reactive sera raises several ques-
tions. This protein could be related to a host immune
response to grafts or transplants ... Its early detection
after transplantation might indicate the implications
of immunosuppression therapy ... The 25-30 kD pro-
tein could therefore be compared with the p28 anti-
gen recently described with human T-cell-related virus
lymphotropic-endogenous sequence ... The character-
ization of this 25-30 kD protein may represent an
important contribution to the detection of HIV-l relat-
ed endogenous retroviruses' (Agbalika et at., 1992).
34
There are many reasons why the p24 detected in
the sera and cultures of haemophiliacs, like the p24
detected in organ recipients may not be the protein of
an exogenous retrovirus, HIV, but either a non-viral-
protein or the protein of an endogenous retrovirus:
1. Like transplant recipients, haemophiliacs receive
material derived from other humans;
2. Like organ transplant recipients, haemophiliacs are
immunosuppressed (see below);
3. HIV cannot be 'isolated' unless the cultures are
mitogenically stimulated (activated);
4. The normal human genome contains many copies
of endogenous retroviral sequences (proviruses),
'including a complex family of HlV-1 relat-
ed sequences' (Horwitz, Boyce-Janino & Faras,
1992), a 'large fraction' of which 'may exist with-
in a host cell as defective genomic fragments. The
process of recombination however may allow for
their expression as either particle or synthesis of
a new protein(s)' (Weiss et al., 1982; Varmus
& Brown, 1989; Cohen, 1993; Lower & Lower,
1993; Minassian et al., 1993). Varmus describes the
genetic behaviour of retroviruses as follows: 'Dur-
ing the virus life cycle, several interesting genetic
and quasi-genetic phenomena may occur, especial-
ly if cells are infected by more than one virus:
production of heterozygotic dimeric genomes, for-
mation of pseudotypes at high frequencies (parti-
cles with core proteins and genome provided by
one virus and envelope proteins by another), fre-
quent deletions and nucleotide substitutions, and
recombination between related, coinfecting virus-
es. [Recombination between retroviruses is surpris-
ingly efficient but its mechanistic basis has not been
resolved], (Varmus, 1988).
5. Cultivation of normal 'non-virus' producing cells
leads to retroviral production (expression), 'the
failure to isolate endogenous viruses from cer-
tain species may reflect the limitations of in vit-
ro cocultivated techniques' (Todaro, Benviste &
Sherr, 1976). The expression can be accelerated
and the yiel~ increased by exposing the cultures to
mitogens, mutagens or carcinogens, co-cultivation
techniques and cultivation of cells with supernatant
from non-virus producing cultures (Toyoshima &
Vogt, 1969; Aaronson, Toduro & Schlonick, 1971;
Hirsch, Phillips & Solnick, 1972). For HlV iso-
lation, in most instances, all the above techniques
are employed. Thus, even if 'true' (Popovic, Sarn-
gadharan & Read, 1984) retroviral isolation can be
achieved from the cultures/co-cultures of tissues
from haemophiliacs, it would be difficult if not
impossible to be certain that the retrovirus in ques-
tion is an exogenous retrovirus which is acquired
through factor VIII administration. For such evi-
dence to be accepted as proof of the existence of
HIV, the activation of an endogenous provirus or
a provirus assembled by recombination of endoge-
nous retroviral and cellular sequences would need
to be rigorously excluded.
Thus, although AIDS researchers acknowledge that:
(a) plasma is 'unlikely to be a meaningful source of
HIV infection';
(b) cell free particles in plasma lack the gp 120 protein
which is 'crucial to HIV's ability to infect new
cells' ;
(c) factor VIII preparations are cell free;
(d) the physical processes employed in the manufac-
ture of factor VIII even in the absence of heating,
destroy both cells and viruses;
AIDS researchers claimed and continue to claim that
'HIV' has been 'isolated' from haemophiliacs. How-
ever, and in spite of this affirmation, the above data
strongly signifies that the HIV phenomena (parti-
cles, RT, antibody-antigen reactions (WB), HIV-PCR-
hybridisation) observed in patients with haemophilia,
whatever they represent, are inconsistent with the par-
enteral acquisition of an exogenous retrovirus.
Lastly, 'HIV' has been 'isolated' from children
with haemophilia:
(a) who had no other risk factor other than haemo-
philia;
(b) where each plasma unit from which factor VIII was
made 'had been tested for HIV antibody, hepatitis
B surface antigen and alanine aminotransferase,
usually within 2 days after collection' (Remis et
al., 1990);
(c) where factor VIII was heat treated at 60°C for 30
hours (according to some authors HIV is 'com-
pletely inactivated in the samples within a few
minutes', of heating (Hilfenhaus et al., 1990»;
(d) where the source plasmas from which the lots of
factor VIII were made were retested 'within several
months after donating factor VIII, and were found
negative' (Neumann et al., 1990; Remis et al.,
1990).
This is as close a proof as one can get that what has been
called HIV infection in haemophiliacs is not caused
by an exogenous retrovirus to which haemophiliacs
have been exposed by the administration of factor VIII
preparations.

T4 cells
It is generally accepted that in patients with haemo-
philia, HIV destroys T4 lymphocytes leading to
acquired immune deficiency. Although this view has
prevailed for ten years, at least one well known group
of researchers of AIDS in haemophiliacs, that from
the University of Bonn, questioned the above relation-
ship between HIV and T4 cells as recently as 1990.
'It is not clear whether the virus-host interrelationship
in HIV infections is regulated primarily by the virus
or by the host; i.e., are CD4+ cells depleted by non-
viral mechanisms and does the virus adjust itself to the
weakened defense? Or is the depletion of CD+ cells
the consequence of the spread and cytopathogenici-
ty of virulent viral variants, which developed at ran-
dom from avirulent precursors?' (Scheneweis et at.,
1990). Discussing their data a year earlier they con-
cluded 'The results suggest that reactivation of HIV
occurs when immune deficiency has become manifest'
(Schneweis et at., 1989). The question whether HIV
leads to T4 cell depletion or conversely whether T4
cell depletion leads to 'HIV infection' (particles, RT
in cultures, antigen/antibody reactions, 'HIVIPCR')
can only be resolved by having direct evidence that
HIV destroys the T4 cells of haemophiliacs. No such
evidence exists. An indirect method of resolution is
the examination of the chronological sequence of HIV
infection and T4 cell depletion. Numerous reports from
many well known researchers of AIDS in haemophil-
iacs have shown that T4 cell depletion precedes 'HIV
infection' :
1. Mortimer and his colleagues state, 'The OKT4 sub-
set was reduced in both seropositive (p < 0.01)
and seronegative (p < 0.05) haemophiliacs but
there was no difference between seropositive and
seronegative patients' (Moffat, Bloom & Mor-
timer, 1985);
2. Weiss and colleagues report, 'We have thus been
able to compare lymphocyte subset data before
and after infection with HTLV-III. It is commonly
assumed that the reduction in T-helper-cell num-
bers is a result of the HTLV-III virus being tropic
for T-helper-cells. Our finding in this study that T-
helper-cell numbers and the helper/suppressorratio
did not change after infection supports our previous
conclusion that the abnormal T-Iymphocyte subsets
are a result of the intravenous infusio~ of factor
VIII concentrates per se, not HTLV-III infection'
(Ludlam et at., 1985);
35
3. Kessler and colleagues found, 'Repeated expo-
sure to many blood products can be associated
with development ofT41T8 abnormalities' includ-
ing 'significantly reduced mean T41T8 ratio com-
pared with age and sex-matched controls' (Kessler
et at., 1983);
4. In 1984, Tsoukasetat. observed that among a group
of33 asymptomatic haemophiliacs receiving factor
VIII concentrates, 66% were immunodeficient 'but
only half were seropositive for HTLV-III', while
'anti-HTLV-III antibodies were also found in the
asymptomatic subjects with normal immune func-
tion'. They summarised their findings as follows:
'These data suggest that another factor (or factors)
instead of, or in addition to, exposure to HTLV-III
is required for the development of immune dys-
function in haemophiliacs' (Tsoukas et at., 1984);
5. By 1986 researchers from the CDC concluded:
'Haemophiliacs with immune abnormalities may
not necessarily be infected with HTLV-IIIILAV,
since the factor concentrate itself may be immuno-
suppressive even wh~n produced from a population
of donors not at tisk for AIDS' (Jason et at., 1986);
6. In 1985 Montagnier (Montagnier, 1985) wrote:
'This [clinical AIDS] syndrome occurs in a minor-
ity of infected persons, who generally have in com-
mon a past of antigenic stimulation and of immune
depression before LAV infection'.
Thus, haemophiliacs may develop immune deficien-
cy before HIV infection, that is, HIV is not necessary
for the decrease in T4 cells observed in haemophili-
acs. Furthermore, to date, there is no evidence either
from the haemophilia studies or from the studies in any
other AIDS risk group, that HIV can induce immune
deficiency (Papadopulos-Eleopulos et at., 1994). In
other words, HIV is neither necessary nor sufficient
for the appearance of immune deficiency (decrease in
T4 cells). However, there is ample evidence which
shows that:
1. Decrease in T4 cells in AIDS patients is not due to
destruction of T4 cells, but due to a change in T8
phenotype (Papadopulos-Eleopulos et at., 1994);
2. There is no correlation between T4 numbers and the
clinical syndrome in any AIDS risk group (Allain
et at., 1987; Papadopulos-Eleopulos et at., 1994).
That is, decrease in T4 cell numbers is neither neces-
sary nor sufficient for the appearance of the clinical
syndrome.
36
Clinical and classification considerations
In 1981, high frequencies of Kaposi's sarcoma (KS),
Pneumocystis carinii pneumonia (PCP) and a small
number of other diseases induced by other opportunis-
tic infectious agents, that is by agents which are ubiq-
uitous but which usually produce clinical disease only
when the host defense mechanisms are depressed, were
observed in gay men in the United States.
Some of the gay men with KS or PCP were test-
ed for immunological abnormalities and a significant
number were found to have low numbers of T4 cells,
'cellular immune deficiency'. Because of this, the term
gay related immune deficiency (GRID) was first used
to describe the disease in these patients, but not long
after this was changed to AIDS. In 1982, the CDC
defined AIDS as
'illnesses in a person who 1) has either biopsy-
proven KS or biopsy- or culture-proven life-
threatening opportunistic infection, 2) is under 60,
and 3) has no history of either immunosuppressive
underlying illness or immunosuppressive therapy'
(CDC, 1982a; 1982b). In addition to PCP, the 'seri-
ous or were 'meningitis, or encephalitis due to
one or more of the following: aspergillosis, can-
didiasis, cryptococcosis, cytomegalovirus, nocar-
diosis, strongyloidosis, toxoplasmosis, zygomyco-
sis, or atypical mycobacteriosis (species other than
tuberculosis or lepral); esophagitis due to candidia-
sis, cytomegalovirus or herpes simplex virus; pro-
gressive multifocal leukoencephalopathy; chron-
ic enterocolitis (more than 4 weeks) due to cryp-
tosporidiosis; or unusually extensive mucocuta-
neous herpes simplex of more than five weeks dura-
tion' .
It must be pointed out that not one of the diseases
which constituted AIDS, the AIDS indicator diseases,
was new. What was new was the high frequency of
these diseases in gay men (CDC, 1982a; 1982b). In
the same year, Robert Gallo, Myron Essex and James
Curran put forward the hypothesis that the cause of
AIDS is a virus, the retrovirus HTLV-l or a simi-
lar virus (Gallo, 1987). According to this theory, the
retrovirus induced immune deficiency by causing the
destruction of T4 cells, which in turn led to the appear-
ance of KS, PCP and other 01, i.e. AIDS. In order to
obtain evidence in support of the above theory, that
AIDS was caused by an infectious agent, the CDC
formed a task-force composed of32 individuals, main-
ly physicians, which 'actively surveyed physicians in
18 major metropolitan areas in the United States by
letter and telephone to inquire about Kaposi's sarcoma
in persons under 60 years of age or opportunistic infec-
tions in patients without a known predisposing factor
since January 1979 ... a formal request was made to
state health departments to notify the CDC of illnesses
suspected of fitting the [above] case definition' (CDC,
1982a). Since HTLV-l was claimed to be transmitted
by blood and blood products, patients with haemo-
philia became a specific target. In July 1982 the CDC
reported the first three cases of 'Pneumocystis carinii
pneumonia among persons with Haemophilia N.
The first patient was a 62 year old individual with
a one year history of weight loss. The treatment and
previous medical history were not given. In Decem-
ber 1981, following the development of cough and
fever he was found to be 'lymphopenic, and chest
X-ray revealed interstitial infiltrates compatible with
viral pneumonia' . He was treated with corticosteroids
resulting in an 'overall clinical improvement' . In Jan-
uary 1982 he presented with 'severe respiratory dis-
tress' and PCP was proven by open lung biopsy.
The second patient, 59 years old, with a histo-
ry of weight loss, 'apthous-like ulcers and anterior
cervical adenopathy beginning in October 1981', was
diagnosed with oropharyngeal candidiasis in Febru-
ary 1982. No previous medical history or treatment
was given. In May 1982 he was hospitalised 'with
symptoms including nausea, vomiting, and recurrent
fever. Pneumonia was diagnosed, and P. carinii and
cytomegalovirus (CMV) were repeatedly identified
from lung tissue or bronchial secretions'. He also had
decreased T4 cell number, increased T8 cell numbers
and a decreased T41T8 ratio.
The third patient, 27 years old, with a history of
fever and urinary frequency and urgency (treatment
not given), was diagnosed with PCP in October 1981.
In February 1982 he was treated with ketoconazole.
By April he developed fever, splenomegaly, anaemia,
lymphopenia, and Mycobacterium avium was grown
from a number of tissues. He also had 'a reduction in
absolute numbers of circulating T-cells' . Subsequently,
he was found to have decreased T4 cells, increased T8
cells and a low T4/T8 ratio.
From these case histories it was concluded that
'the clinical and immunological features of these
three patients are strikingly similar to those recently
observed among certain individuals from the following
groups: homosexual males, heterosexuals who abuse
IV drugs, and Haitians who recently entered the United
States. Although the cause of the severe immune dys-

function is unknown, the occurrence among the three
hemophiliac cases suggests the possible transmission
of an agent through blood products' (CDC, 1982a;
1982b).
As a consequence, the CDC 'notified directors of
hemophilia centers about these cases and, with the
National Hemophilia Foundation, has initiated collab-
orative surveillance'. In the same year, Ragni and col-
leagues found two haemophiliacs with decreased T4
and increased T8 cell numbers, elevated IgG and IgM
levels and lymphadenopathy and concluded that their
findings were 'consistent with the diagnosis of AIDS'
(Ragni et al., 1983).
By October 1983, the CDC had 23 reports of AIDS
cases in haemophiliacs, 18 in the USA and 5 other
countries, none with KS. Two of the above cases had
other risk factors, one was an IV user, the other gay
(Jason et al., 1984). By the end of 1984, the number
of haemophilia AIDS cases increased to 67 (Levine,
1985). By this time, Gallo's claim that AIDS in all risk
groups - gay men, IV users, blood transfusion recip-
ients, and haemophiliacs - is caused by a new retro-
virus, H1LV-III, later renamed HIV, became generally
accepted. By the end of June 1985, 80 haemophili-
acs in the USA and five in the United Kingdom were
reported with AIDS, none with KS (Jones etat., 1985).
At about the same time it became known that by 1982
the vast majority of haemophiliacs tested positive for
HIV. 'Yet the attack rate of AIDS in hemophiliacs is
not steadily climbing per reported period [in gay men it
was increasing exponentially]. In addition, the last two
reporting periods [last quarter of 1984, and first quar-
ter of 1985 when HIV testing was introduced] contains
a disproportionate number of patients with mild and
moderate disease' (Levine, 1985). Indeed, as has been
seen, the only clinical symptoms in the two patients
reported by Ragini el al. consistent with the 'diagnosis
of AIDS' was lymphadenopathy.
Some published reports represent the gallant efforts
made by some researchers to prove that HIV infection
in haemophiliacs, like HIV infection in gay men, leads
to neurological complications. Researchers from the
Royal Postgraduate Medical School in London report-
ed two fatal haemophilia cases. The first patient exhib-
ited 'lethargy, poor concentration, and difficulty with
micturition. Examination disclosed diminished cogni-
tive function and brisk reflexes. Computed tomogra-
phy (CT) of the brain showed dilated lateral ventri-
cles and widened sulci consistent with cerebral atro-
phy'. Four months later 'he was incontinent and had
difficulty walking and showed signs of a pyramidal
37
tract lesion' . One month later he was 'unable to walk,
had paranoid delusions. Relentless neurological dete-
rioration followed with painful spastic quadriparesis
and convulsions'. The second patient showed 'weight
loss, confusion, unilateral cerebellar dysfunction, and
diplopia which was diagnosed clinically as an internu-
clear opthalmoplegia. A cerebral CT scan showed low
attenuation areas in the white matter of the frontal lobes
and also in the right parietal lobe' . The above clinical
signs were followed by coma. Although no general
or neuropathological examination was conducted in
either of these patients (permission for autopsy was
refused), both these cases of 'subacute encephalopa-
thy' were attributed to HIV because the patients were
HIV positive and had a low T4ff8 ratio (Rahemtulla,
Durrant & Hows, 1986). Similarly, cerebral toxoplas-
mosis attributed to HIV, also without neuropathologi-
cal examination, has also been reported in haemophil-
iacs (Esiri et at., 1989).
The introduction of 'mild and moderate disease' as
indicating AIDS, which commenced in the last quarter
of 1984, coincided with the acceptance of HIV as the
cause of AIDS in all risk groups and the redefinition
of AIDS by the CDC. Before this date practically all
AIDS was KS and PCP. According to the 1985 CDC
definition, 'a case of acquired immunodeficiency syn-
drome (AIDS) is an illness characterized by:
I. one or more of the opportunistic diseases listed
below (diagnosed by methods considered reliable)
that are at least moderately indicative of underlying
cellular immunodeficiency; and
II. absence of all known underlying causes of cel-
lular immunodeficiency (other than LAVIH1LV-
III infection) and absence of all other causes of
reduced resistance reported to be associated with
at least one of those opportunistic diseases.
Despite having the above, patients are excluded
as AIDS cases if they have negative result(s) on
testing for serum antibody to LAVIH1LV-I1I, do
not have a positive culture for LAV/H1LV-I1I, and
have both a normal or high number of T-helper
(OKT4 or LEU3) lymphocytes and a normal or
high ratio of T-helper to T-suppressor (OKT8 or
LEU2) lymphocytes. In the absence of test results,
patients satisfying all other criteria in this definition
are included as cases' (WHO, 1986).
A number of additional AIDS indicator diseases were
added to the 1982 definition. These included: lym-
phoma limited to the brain, disseminated histoplas-
mosis, isosporiasis and non-Hodgkin's lymphoma.
Although HIV was accepted as being the cause of
38
AIDS in all AIDS risk groups, there were significant
differences between the groups. For example:
1. If mv is the cause of AIDS in all the above risk
groups, one would expect the rate of conversion
to clinical AIDS in all HIV positive individuals
to be the same. This is not the case. In a cohort
of gay men in the USA, the three year actuarial
progression rate was 22% (Moss et al., 1988). In
a cohort of haemophiliacs, the annual incidence of
AIDS ranged from zero during the first year after
seroconversion to 7% during the eight year follow
up with an eight year cumulative rate of 13.3%
(Goedert et at., 1989). In the United Kingdom three
percent of haemophilia patients developed AIDS
by three years after seroconversion and 7% by five
years post seroconversion (Darby et at., 1989);
2. The clinical syndrome in haemophiliacs is differ-
ent from that in gay men. KS, one of the two most
significant and frequent diseases in gay men, for
whose explanation the HIV hypothesis was put for-
ward, is practically non-existent in haemophiliacs.
Such is also the case with oral hairy leukoplakia
(Greenspan & Greenspan, 1989).
To determine the forms of neuropathological and sys-
temic pathology in mv positive haemophiliacs as
compared to other HIV positive subjects, Esiri et at.
examined the brains of 42 HIV seropositive HIV indi-
viduals. Among these were 11 haemophiliacs and 29
gay men. Four of the haemophiliacs were classified as
having AIDS, as were the majority of the gay men.
'The prevalences of opportunistic infections of the
central nervous system were significantly higher in
non-haemophiliacs (cerebral toxoplasmosis 23% (7),
progressive multifocalleucoencephalopathy 10% (3),
and cerebral cytomegalovirus infection 19% (6) in the
non-haemophiliacs v no cases in the haemophiliacs).
The prevalences of fresh and old intracranial haem-
orrhages and cirrhosis of the liver were significantly
higher in the haemophiliacs (fresh intracranial haemor-
rhage 45% (5), old intracranial haemorrhage, 36% (4)
and cirrhosis of the liver 27% (3) in the haemophiliacs
v no cases in the non-haemophiliacs), . Discussing their
results Esiri and colleagues wrote: 'The rarity of oppor-
tunistic infections in the central nervous system and
elsewhere in haemophiliacs is in keeping with many of
them dying at an earlier (pre-AIDS) stage in the devel-
opment of HIV associated immunodeficiency than do
most subjects with HIV infection. [To the contrary, as
has been stated above, HIV seropositive haemophiliacs
live longer than HIV seropositive gay men]. Consis-
tent with this suggestion is Hilgartner's view that the
pattern of disease due to HIV infection in haemophil-
iacs differs from that in other groups at high risk, and
from the observation of Darby et at. that a substantial
burden of fatal disease occurs among haemophiliacs
who are positive for HIV and not formally diagnosed
as having AIDS. If our cases of haemophiliacs are rep-
resentative of others much of this fatal disease would
seem to be accounted for by cerebrovascular and liver
disease' (Hilgartner, 1987; Esiri et at., 1989; Darby et
at:, 1990).
Once again, it is of pivotal significance to note that
even in the early years of the recognition of AIDS,
it was agreed that in haemophiliacs, there was 'an
immunodeficiency independent of HTLV-III infection'
(Hollan et at., 1985; Madhok et at., 1986). That is,
haemophiliacs have 'known underlying causes to cel-
lular immunodeficiency (other than LAVIHTLV-II1),
HIV'. Thus, according to the 1985 AIDS definition,
haemophiliacs cannot be AIDS cases. Furthermore,
although a prerequisite of the diagnosis of AIDS in
the 1985 definition was a positive test for HIV, of all
AIDS cases reported in the two year period 1985-1987
in New York City and San Francisco, which constituted
approximately one third of all AIDS cases in the USA,
'less than 7% have been reported with HIV-antibody
test results' (CDC, 1987).
Like the 1982 definition, the 1985 required the dis-
eases which constituted AIDS, the AIDS 'indicator'
diseases, to be definitely diagnosed. However, the New
York State Health Department found that although
13% of 1329 AIDS cases reported by the beginning
of 1987 did have a positive mv antibody test, clini-
cally these individuals' symptoms were suggestive of
AIDS but were not definitely diagnosed. In a similar
study researchers from the CDC and the Departments
of Health in New Jersey, Puerto Rico, Boston, Wash-
ington, D.C. and Connecticut found that approximate-
ly 11 % of cases had a presumptive diagnosis because,
according to one AIDS epidemiologist 'Many physi-
cians are familiar enough with AIDS now that when
they see a young man with pneumonia, they can make
a reasonable presumptive diagnosis [of PCP] without
resorting to biopsy,' (Anonymous, 1987). Thus a sig-
nificant number of reported AIDS cases did not meet
either the 1982 or the 1985 AIDS definition.
To accommodate the non-compliance with the 1985
AIDS definition, the CDC claimed that their 1985 def-
inition made it 'unnecessarily difficult to diagnose'
AIDS, and thus it underestimated the number of AIDS
cases. In 1987, the CDC yet again redefined AIDS.
The 1987 definition permitted reporting of Acquired

Immunodeficiency (AIDS) cases even if there was no
evidence of immune deficiency or of a definite diag-
nosis of at least some of the AIDS indicator diseases.
More importantly, although the definition considered
HIV to be the sole cause of AIDS, individuals could be
reported as AIDS cases even when there was evidence
against HIV infection. The major features of the 1987
definition are:
I. Without laboratory evidence of HIV infection
(patients not tested for HIV or if tested the results
were inconclusive), the 1985 indicator diseases 'if
reliably diagnosed and other causes of immune
deficiency are ruled out', (that is, immunosup-
pressive therapy ~ 3 months before the onset of
the indicator disease, a small number of neoplastic
diseases diagnosed ~ 3 months after diagnosis of
the indicator disease, an even a smaller number of
congenital immunodeficiency diseases), 'are still
accepted as a diagnosis of AIDS'.
II. 'Regardless of the presence of other causes of
immunodeficiency in the presence of laboratory
evidence of HIV infection' :
A. Twelve new AIDS indicator diseases, when def-
initely diagnosed, indicate AIDS. These include:
(i) extrapulmonary tuberculosis;
(ii) wasting syndrome, that is, involuntary weight
loss of > 10% of body weight and either chronic
diarrhoea (at least 2 stools per day for ~ 30 days) or
chronic weakness and documented fever (for ~ 30
days, intermittent or constant);
(iii) HIV encephalopathy (schizoid behaviour, gen-
eral fatigue, malaise, diminished cognitive func-
tion) (Gomperts, 1990);
(iv) bacterial infections, multiple or recurrent (any
combination of at least two within a 2-year period)
of the following types affecting a child less than 13
years of age: septicaemia, pneumonia, meningitis,
bone or joint infection, or abscess of an internal
organ or body cavity (excluding otitis media or
superficial skin or mucusal abscesses) caused by
Haemophilus, Streptococcus, (including Pneumo-
coccus, or other pyogenic bacteria.
B. The diseases listed below, even if presumptively
diagnosed, indicate AIDS:
'1. Candidiasis of the oesophagus.
2. Cytomegalovirus retinitis with loss of vision.
3. Kaposi's sarcoma.
4. Lymphoid interstitial pneumonia and/or pul-
monary lymphoid hyperplasia (LIPILPH complex)
affecting a child < 13 years of age.
5. Mycobacterial disease (acid-fast bacilli with
39
species not identified by culture), disseminated
(involving at least 1 site other than or in addition
to lungs, skin, or cervical or hilar lymph nodes).
6. Pneumocystis carinii pneumonia.
7. Toxoplasmosis of the brain affecting a patient
> 1 month of age.' For example:
(i) presumptive diagnosis of candidiasis of the
oesophagus is:
'A recent onset of retrosternal pain on swallow-
ing; AND oral candidiasis diagnosed by the gross
appearance of white patches or plaques on an ery-
thematous base or by the microscopic appearance
offungal mycelial filaments in an uncultured spec-
imen scraped from the oral mucosa' .
(ii) presumptive diagnosis of KS is:
'A characteristic gross appearance of an erythe-
matous or violaceous plaque-like lesion on skin or
mucous membrane'
(WHO,1988).
III. If there is 'laboratory evidence against HIV infec-
tion' , that is, the laboratory tes!§ for HIV infection
are negative, but the patient has all above men-
tioned causes of immunodeficiency excluded and
either:
(a) Pneumocystis carinii pneumonia diagnosed by
a definite method OR;
(b) any of the 1985 AIDS indicator disease diag-
nosed by a definite method AND;
(c) a T4 cell count < 400/mm3
the-patient has AIDS.
Thus the 1987 AIDS definition legitimised the report-
ing of a person as suffering from Acquired Immune
Deficiency Syndrome, accepted to be caused by HIV
when;
1. Evidence of HIV infection was 'not performed or
gave inconclusive results', or even when all tests
were negative, i.e. when there was definite evi-
dence that the patient was not infected with HIV;
2. The absence of any evidence of immune deficiency
and even when the cause of immune deficiency
could have been other than HIV;
3. Both in the absence of HIV infection and immune
deficiency.
In 1987, it was known that many indicator dis-
eases of the 1985 definition, including KS and
PCP, were difficult to diagnose both clinically and
histopathologically (CDC, 1981; Follansbee et ai.,
1982; Hughes, 1987; ~eral et ai., 1990). Yet the
definition permitted a person to be reported as suf-
fering from AIDS, even when the indicator diseases
were presumptively diagnosed, i.e. on the basis
40
of non-specific findings. In fact, the 1987 defi-
nition allowed so many degrees of freedom that
nearly anybody, especially those belonging to a
'risk group', could be reported as an AIDS case.
This can best be illustrated by the following exam-
ple:
In 1992, 'The AIDS Reporting System was
searched for all persons who had been given a
diagnosis of AIDS' by investigators from the CDC
(Smith et at., 1993). In seven reported haemophilia
'AIDS' cases:
(a) the HIV tests were all negative;
(b) not one of the patients had an AIDS indicator
disease: four had common diseases especially
frequent in haemophiliacs: haematomas, hep-
atitis C infection, thrombocytopenia and oral
herpes. Two patients were asymptomatic;
(c) all patients had a low « 300/mm3) T4 cell
count.
Interestingly, in 1987, merely by redefining AIDS,
there was a sharp increase in AIDS cases in all AIDS
risk groups including haemophiliacs. In 1988, there
were 552 cases in haemophiliacs of which 31 were
known to be gay and 12 drug users (Koerper, 1989).
Not only did the 1987 AIDS definition fail to solve
the major problems arising from the 1982 definition,
but by then other problems associated with the HIV
hypothesis of AIDS in haemophiliacs became appar-
ent:
1. It is accepted by all HIV researchers that heating
factor VIII preparations destroys HIY. Yet AIDS
has been diagnosed in haemophiliacs who exclu-
sively received heat treated factor VIII (CDC,
1987);
2. Unlike other AIDS risk groups, in haemophilia,
thrombocytopenia and older age are risk factors
for the development of AIDS (Eyster et at., 1987).
However:
(a) it is well known that older age is associated
with both immune deficiency and increased inci-
dence of 01 and malignancies. Indeed, of the
first three cases reported to the CDC with PCP
in haemophiliacs in 1982, one of these was not
considered to be an AIDS case because he was
62 years of age;
(b) before the AIDS era the rate of thrombocyto-
penia in haemophiliacs was significantly differ-
ent (p < 0.0003) than the normal population.
Eyster et at. examined data collected by the
Hemophilia Study Group from 1975 to 1979
on 1551 patients, 'To determine whether there
was clinical or laboratory evidence to suggest
an abnormality of immunoregulation in per-
son with haemophilia before the recognition of
AIDS'. Twenty-six of 518 (5%) patients whose
platelet number were determined were found to
be thrombocytopenic (four developed idiopath-
ic thrombocytopenic purpura [ITP]) and 9.3%
(9411013) had lymphocytopenia (Eyster et al.,
1985);
(c) to elucidate 'The attention given to infectious
diseases in haemophiliacs', which has 'given
rise to the concept of a novel form of "immuno-
suppression" in this population group', Aron-
son obtained data from the National Center for
Health Statistics USA regarding primary and
associated causes of death in haemophiliacs. For
the years 1968-79, 949 deaths were record-
ed, '2 patients had candidiasis listed as the
primary cause of death. 66 deaths were relat-
ed to pneumonia (10 primary, 56 associated)
usually from unidentified organisms. Many of
these pneumonia-associated deaths occurred in
the younger age groups (25/66 [38% 1 were in
patients below the age of 45 while only 8% of
pneumonia deaths in the normal male popula-
tion are below the age of 45)'. Aronson conclud-
ed 'it seems possible that many of the unspec-
ified pneumonias in haemophiliacs in the past
would be classified today as AIDS' (Aronson,
1983). 'Death reports from the United States
Vital Statistics System and from the hemophil-
ia center survey' for the above period 1968-
1979 were also analysed by workers from the
CDC and the National Hemophilia Foundation.
They found that 'an average of six deaths were
reported to the National Center for Health Statis-
tics annually in 1968-1979 for conditions which
could possibly be related to AIDS' (Johnson
et at., 1985). Of 89 haemophilia deaths in the
UK between 1976 and 1980, 11 (12%) died
of unknown causes, 4 (4.5%) of unspecified
pneumonias and 7 (8%) of neoplasms (Rizza &
Spooner, 1983).
Thus, AIDS-like diseases in an appreciable number
of haemophiliacs were reported before the AIDS era,
1980. A high frequency of reporting, or even true inci-
dence of these diseases in this group since 1980 may
be due to a number of factors other than HIV:
1. Underreporting of specific causes of death in
haemophilia patients before 1980. In the above
mentioned survey by workers from the CDC and

the National Hemophilia Foundation it was found
that 'The number of deaths reported among factor
VIII-deficient patients in the hemophilia treatment
survey decreased from 26 deaths and 24 deaths in
1978 and 1979 respectively, to 18 and 19 deaths in
1980 and 1981, respectively. The number of deaths
then more than doubled, with 53 deaths report-
ed for 1982. The two- to three-fold increase in
deaths in 1982 include the first five reported of
immunodeficiency, an increase in deaths assigned
to haemorrhage unrelated trauma, and an increase
in deaths unrelated to AIDS or hemophilia. The
sharp increase in deaths across all categories is
most likely due to underreporting of deaths, as a
result of hemophilia treatment centers inability to
identify deaths in previous years' (Johnson et at.,
1985);
2. The increased reporting of PCP in haemophiliacs
may be due to a true increase of the incidence of
PCP or due to:
(a) under-diagnosis of PCP in this population
before 1980 as a result of:
(i) lack of awareness; one searched for PCP
only in immunosuppressed patients, but before
1980 no one was aware that haemophiliacs
were immunosuppressed (no immunological
tests were carried out in this population);
(ii) the inadvisability, in haemophiliacs, of
performing invasive procedures which were
required for definitive diagnosis;
(b) in the AIDS era, overdiagnosis of PCP after
1980, that is, pneumonias of unknown aetiology
are presumed to be PCP. Even when pneumonias
are 'definitely diagnosed' as PCP, this may not
be the case: 'one might expect to find P. carinii in
the fluids from bronchoalveolar lavage of about
40 percent of patients with AIDS who present
with symptomatic pneumonia caused by other
organisms' (Hughes, 1987). However, regard-
ing the method for definite diagnosis of PCP,
the CDC definition states: 'Pneumocystis carinii
pneumonia (on histology, or microscopy of a
"touch" preparation, bronchial washings or spu-
tum)' (WHO, 1986);
3. Over-diagnosis of AIDS cases. For example,
between July 1986 and June 1987, the CDC had
3001 death certificates 'that indicated HIV infec-
tion/AIDS', but only 85% met the CDC AIDS def-
inition (CDC, 1991);
4. Increased life span of patients with haemophilia.
PCP 'in infants and children with congenital
41
immunodeficiency did not evolve until after the
development of antibiotic therapy which allowed
these children to live long enough to develop a non-
bacterial infection' (Burke & Good, 1973). That
this may also be the case in haemophiliacs is sug-
gested by the following:
(a) in haemophiliacs the risk of AIDS is directly
related to age. In one USA study, eight-year
cumulative incidences of AIDS in HIV positive
haemophiliacs have been found to be as follows:
1-11 years old, 3%; 12-17 years old, 9.2%; 18-
25 year old, 14.9%; 26-34 years old, 19% and
35-70 years old, 29.7% (Goedert et at., 1989).
The CDC also reported that the AIDS patients
are 'older than the other haemophilia treatment
center patients (p < 0.005), with a median age
of 34 years' (Johnson et at., 1985);
(b) before the AIDS era, the life span of patients
with haemophilia was much lower than that of
the rest of the population, in 1972 the median age
was 11.5 years. This compared with a median
age of 26.8 years for the USA male population
in 1970. As a result of treatment with factor VIII
the median age increased to 20 years in 1982,
and was 25 years in 1988 (Johnston et at., 1985;
Koerper, 1989);
5. 'Because of advances in medical practice' in the
last few decades, there has been an increase in
the incidence of immunosuppression and DIs. This
may especially be expected in haemophiliacs since
steroids have been used for the treatment of joint
problems (Muller, 1960), for factor VIII inhibitors
(Lian, Larcada & Chiu, 1989) and for ITP (Eyster et
at., 1985), all of which are present in haemophilia
patients more often than in the general population.
Joint problems have also been treated with oth-
er immunosuppressive agents such as radioactive
gold or technetium (Fernandez-Palazzi, de Bosch
& de Vargas, 1984). In fact, before the AIDS era,
'Pretreatment with antihistamines, corticosteriods
and adrenergic agents was recommended for all
patients with hemophilia being treated at home'
with factor VIII (Helmer et at., 1980);
6. HIV positive individuals including haemophiliacs
are treated with AZT. The toxic effects of AZT have
repeatedly been stressed by Lauritsen (1990) and
Duesberg (1992). Here, only some of these proper-
ties, especially those of significance to haemophil-
iacs, will be mentioned:
(a) bone marrow failure including anaemia, neu-
tropenia and thrombocytopenia (Callaham,
42
1991). Many patients require blood transfusion
within weeks of commencing AZT. It is impor-
tant to note that 'the frequency of lymphocy-
topenia and thrombocytopenia was increased in
multitransfused factor VITI-deficient hemophil-
iacs before the advent of AIDS' and that the
latter is a contributing factor in the development
of AIDS in haemophilia (Eyster et aI., 1985).
Furthermore, haemophiliacs with thrombocyto-
penia 'usually need treatment with drugs as
zidovudine, corticosteroids or immunoglobu-
lins, which interfere with the immune system'
(Mannucci et al., 1992).
(b) peripheral neuropathy;
(c) myopathy: 'up to one-third of patients taking the
drug for more than a year, at a dose of around Ig
daily, develop myopathy'. It is manifested clin-
ically as symmetrical proximal weakness, usu-
ally preceded by and associated with myalgia,
together with muscle wasting. This leads to dif-
ficulty in walking and patients become wheel-
chair or bed-bound (Lane et al., 1993). The
toxic effects on muscle eventually lead to heart
and other cardio-vascular and pulmonary prob-
lems. Since the major long term disabilities in
haemophiliacs, irrespective of AIDS, are mus-
culoskeletal disease (Levine, 1985), the above
toxic effects of AZT are of particular interest in
this group of individuals.
(d) In the 1960s, before the AIDS era, AZT was
developed as an agent to treat neoplasms. All
drugs presently used to treat cancer are known to
be immunosuppressive and to lead to the appear-
ance of OI. They are also known to be carcino-
genic (Papadopulos-Eleopulos, 1982). Before
the AIDS era animal evidence showed that
AZT is no exception (Callaham, 1991) and the
widespread use of AZT in HIV positive indi-
viduals in the AIDS era has shown that this is
also the case in humans. Thus lymphomas devel-
op in 9% 'of AZT-treated AIDS patients, with
Kaposi's sarcoma, pneumonia and wasting dis-
ease' within one year of commencing therapy
and it has been calculated that the 'annuallym-
phoma risk of AZT recipients is about 30 times
higher than that of untreated HIV-positive coun-
terparts' (Duesberg, 1992).
(e) AZT induces liver damage and may cause hep-
atic failure and death (Touchette, 1993). This
is of particular interest in haemophiliacs who,
regardless of their HIV status, can suffer from
chronic liver disease, which may also 'contribute
to AIDS-related diseases', and since the intro-
duction of factor VIII for the treatment of bleed-
ing, has become the leading cause of death in
haemophiliacs (Eyster et aI., 1985; 1987).
7. Factor VIII. As Levine has pointed out: 'To under-
stand the occurrence of AIDS in haemophilia, it
is important to recognize that each vial of fac-
tor VIII concentrate will contain, depending on
manufacture and lot number, a distillate of clot-
ting factors, alloantigenic proteins, and infectious
agents obtained from between 2,500 and 25,000
blood or plasma donors. Until recently, of all the
protein injected in 'factor VIII preparations', fac-
tor VIII accounted for only about 0.03-0.05% of
the total. The rest included: albumin, fibrin(ogen),
immunoglobulins and immune complexes (Eyster
& Nau, 1978; Mannucci et al., 1992). Even the
recent 'high-purity' factor VIII contains 'potential-
ly harming proteins' such as isoagglutinins, fib-
rin(ogen), split products, immunoglobulins and,
when monoclonal antibodies are used for factor
VIII preparation, murine protein in addition to
albumin (Beeser, 1991).
Factor VIII was first introduced in the late 1960s. 'In
1975, the average patient received an estimated 40,000
units of factor VIII per year (a unit being the equiva-
lent of 1 mL of fresh frozen plasma as to factor VIII
content). By 1981, the average patient was consuming
60,000 to 80,000 units per year' (Levine, 1985). The
introduction of factor VIII led to a dramatic decrease in
haemophilia deaths from bleeding but it also had some
harmful effects including myocardial ischaemia, visu-
al disturbances, headache, dyspnoea, bronchospasm,
hypotension and anemia (Eyster & Nau, 1978; Kopit-
sky & Geitman, 1986; Beeser, 1991). As previously
stated, factor VIII preparations contain immunoglob-
ulin which may produce systemic reactions such as
pruritus, chills, fever, tremor, flushing, malaise, nau-
sea, vomiting, back pain and joint pain (van Aken,
1991). Before the AIDS era, no immunological studies
were carried out in haemophiliacs but subsequently,
as has been mentioned, in 1985 Eyster et al. showed
that frequency of lymphocytopenia and thrombocyto-
penia was increased in haemophiliacs prior to the
AIDS era (Eyser et al., 1985). More recently per-
formed immunological studies, including determina-
tion of T4 cell numbers, led to the generally accept-
ed view that factor VIII itself is immunosuppressive.
Recently, researchers from the UK showed that pro-
gression to AIDS in HIV seropositive haemophiliacs

is determined by abnormalities induced by factors oth-
er than HIV, all of which existed before seroconversion
(Simmonds et ai., 1991). In other words, HIV is not
sufficient for the development of AIDS in patients with
haemophilia.
In conclusion, HIV is not necessary for the develop-
ment of AIDS in patients with haemophilia. Nonethe-
less, since:
1. According to the new 1993 CDC AIDS definition,
any individual who is HIV seropositive and who
has one ('the lowest accurate, but not necessari-
ly the most recent') T4 cell count less than 200
cells!j.tL, irrespective of the clinical situation even
if asymptomatic, has AIDS (CDC, 1992) and,
2. (a) most haemophiliacs test positive for HIV (but
AIDS experts accept that in haemophiliacs a posi-
tive antibody test does not prove HIV infection);
(b) most haemophiliacs have a low number of T
cells (but AIDS experts accept that in haemophili-
acs the immune deficiency may be caused by fac-
tors other than HIV);
in the future, by definition, virtually all haemophiliacs
will die from no other disease but AIDS caused by
HIV.
Note added in proof
After this paper was accepted for publication the CDC forwarded
the authors a copy ofits fact sheet (CDC 1994) on HIV transmis-
sion. Given the perilous future for haemophilia patients enshrined
in the CDC's 1993 AIDS definition and cognisant of the fact that
factor VIII has long been supplied as a freeze-dried powder which
may spend many weeks or months waiting use, it is incomprehensi-
ble that the CDC would also, in 1994, communicate the following
experimental data and conclusion: "In order to obtain data on the
survival of HIV, laboratory studies have required the use of artifi-
cially high concentrations of laboratory grown virus ... the amount
of virus studied is not found in human specimens or anyplace else in
nature, ... it does not spread or maintain infectiousness outside its
host. Although these unnatural concentrations of HIV can be kept
alive under precisely controlled and limited laboratory conditions,
CDC studies have shown that drying of even these high concentra-
tions of mv reduces the number of infectious viruses by 90 to 99
percent within several hours. Since the HIV concentrations used in
laboratory studies are much higher than those actually found in blood
or other body specimens, drying of mY-infected human blood or
other body fluids reduces the theoretical risk of environmental trans-
mission to that which has been observed- essentially zero". It is thus
inexplicable, given their own data, that the CDC continues to regard
patients with haemophilia at risk for H1V infection via contaminated
factor VIII concentrates and enigmatic that another explanation for
'HIV' and AIDS in haemophiliacs has not been sought.
43
Acknowledgements
We would like to thank all our colleagues and especially Richard
Fox, Wendy Erber, Michael Ristow, Stephan Lanka, Alfred Hassig,
Neville Hodgkinson, Christine Johnson, Fabio Franchi, Cecily Met-
calf, Philip Adams, Barry Page, Livio Mina, Gary James, Iris Peter,
the staff of the Royal Perth Hospital Library and the clerical staff
of the Department of Medical Physics. We also thank Harvey Bialy,
Udo Schiilenk, Charles Thomas, Gordon Stewart, James White-
head and Katrina Prastidis for continual encouragement, and Peter
Duesberg for inviting us to submit this paper to Genetica.
We especially thank Michael Verney-Elliot, Joan Shenton and
Bruce Hedland-Thomas for their help and motivating encourage-
ment.
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P. H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 49-68, 1996. 49
© 1996 Kluwer Academic Publishers.

Foreign-protein-mediated immunodeficiency in hemophiliacs with and

without HIV

Peter H. Duesberg
Dept. of Molecular and Cell Biology, Stanley Hall, University of California at Berkeley, Berkeley, CA 94720, USA

Received 10 June 1994 Accepted 6 July 1994

Abstract

Hemophilia-AIDS has been interpreted in terms of two hypotheses: the foreign-protein-AIDS hypothesis and
the Human Immunodeficiency Virus (HIV)-AIDS hypothesis. The foreign-protein-AIDS hypothesis holds that
proteins contaminating commercial clotting factor VIII cause immunosuppression. The foreign-protein hypothesis,
but not the HIV hypothesis, correctly predicts seven characteristics of hemophilia-AIDS: 1) The increased life
span of American hemophiliacs in the two decades before 1987, although 75% became infected by HIV -
because factor VIII treatment, begun in the 1960s, extended their lives and simultaneously disseminated harmless
HIV. After 1987 the life span of hemophiliacs appears to have decreased again, probably because of widespread
treatment with the cytotoxic anti-HIV drug AZT. 2) The distinctly low, 1.3-2%, annual AIDS risk of hemophiliacs,
compared to the higher 5-6% annual risk of intravenous drug users and male homosexual aphrodisiac drug users
- because transfusion of foreign proteins is less immunosuppressive than recreational drug use. 3) The age
bias of hemophilia-AIDS, i.e. that the annual AIDS risk increased 2-fold for each 10-year increase in age -
because immunosuppression is a function of the lifetime dose of foreign proteins received from transfusions. 4)
The restriction of hemophilia-AIDS to immunodeficiency diseases - because foreign proteins cannot cause non-
immunodeficiency AIDS diseases, like Kaposi's sarcoma. 5) The absence of AIDS diseases above their normal
background in sexual partners of hemophiliacs - because transfusion-mediated immunotoxicity is not contagious.
6) The occurrence of immunodeficiency in HIV-free hemophiliacs - because foreign proteins, not HIV, suppress
their immune system. 7) Stabilization, even regeneration, of immunity of HIV-positive hemophiliacs by long-term
treatment with pure factor VIII. This shows that neither HIV nor factor VIII plus HIV are immunosuppressive by
themselves. Therefore, AIDS cannot be prevented by elimination of HIV from the blood supply and cannot be
rationally treated with genotoxic antiviral drugs, like AZT. Instead, hemophilia-AIDS can be prevented and has
even been reverted by treatment with pure factor VIII.

1. The drug- and hemophilia-AIDS epidemics in
America and Europe
About 30 previously known diseases are now called
AIDS if they occur in the presence of antibody against
human immunodeficiency virus (HIV) (Institute of
Medicine, 1988; Centers for Disease Control and Pre-
vention, 1992). These diseases are thoughtto be conse-
quences for an acquired immuno deficiency syndrome
and hence are grouped together as AIDS (Institute of
Medicine, 1988). From its beginning in 1981, AIDS
has been restricted in America and Europe to specific
risk groups (Centers for Disease Control, 1986; World
Health Organization, 1992b). Currently, over 96% of
all American AIDS cases come from AIDS risk groups,
rather than from the general population (Centers for
Disease Control, 1993). These include over 60% male
homosexuals who have been long-term oral users of
psychoactive and aphrodisiac drugs, 33% mostly het-
erosexual, intravenous drug users and their children,
2% transfusion recipients, and about 1% hemophiliacs
(Duesberg, 1992a; Centers for Disease Control, 1993).
Altogether, about 90% of all American and European
AIDS patients are males (World Health Organization,
1992a; Centers for Disease Control, 1993).
Each risk group has specific AIDS diseases. For
example, Kaposi's sarcoma is almost exclusively seen
in male homosexuals, tuberculosis is common in intra-
50
venous drug users, and pneumonia and candidiasis are
virtually the only AIDS diseases seen in hemophiliacs
(Duesberg, 1992a).
In view of these epidemiological and clinical crite-
ria, American and European AIDS has been interpreted
alternatively as an infectious and a non-infectious epi-
demic by the following hypotheses:
1) The virus-AIDS hypothesis. This hypothesis pos-
tulates that all AIDS is caused by the retrovirus HIV,
and thus an infectious epidemic. The inherent danger
of a transmissable disease quickly promoted the HIV
hypothesis to the favorite of 'responsible' health care
workers, scientists and journalists (Booth, 1988). For
example, a columnist of the New York Times wrote
in July 1994 that all non-HIV AIDS science is 'cru-
elly irresponsible anti-science' (Lewis, 1994). And
the retrovirologist David Baltimore warned in Nature
'There is no question at all that HIV is the cause of
AIDS. Anyone who gets up publicly and says the oppo-
site is encouraging people to risk their lives'. (Macil-
wain, 1994).
Moreover, the U.S.' Centers for Disease Control
(CDC) have favored the HIV-AIDS hypothesis from
the beginning (Centers for Disease Control, 1982;
Shilts, 1985; Centers for Disease Control, 1986;
Booth, 1988; Oppenheimer, 1992), because - accord-
ing to Red Cross official Paul Cumming in 1983 - 'the
CDC increasingly needs a major epidemic to justify its
existence' (Associated Press, 1994). Indeed, there has
been no viral or microbial epidemic in the U.S. and
Europe since polio in the 1950s. All infectious diseases
combined now account for less than 1% of morbidi-
ty and mortality in the Western World (Cairns, 1978).
And the control of infectious diseases is the primary
mission of the CDC.
2) The drug-AIDS hypothesis. This hypothesis holds
that AIDS in the major risk groups is caused by
group-specific, recreational drugs and by anti-HIV
therapy with cytocidal DNA chain terminators, like
AZT, and is tr.us not infectious (Lauritsen & Wil-
son, 1986; Haverkos & Dougherty, 1988; Duesberg,
1991, 1992a; Oppenheimer, 1992). The drug-AIDS
hypothesis was favored by many scientists, includ-
ing some from the CDC, before the introduction
of the HIV-AIDS hypothesis in 1984 (Marmor et
aI., 1982; Mathur-Wagh et aI., 1984; Haverkos
et at., 1985; Mathur-Wagh, Mildvan & Senie,
1985; Newell et at., 1985; Haverkos & Dougher-
ty, 1988; Duesberg, 1992a; Oppenheimer, 1992).
3) The Joreign-protein-hemophilia AIDS hypothesis.
This hypothesis holds that hemophilia-AIDS is caused
by the long-term transfusion of foreign proteins con-
taminating factor VIII and other clotting factors and
thus not infectious. This hypothesis also preceded the
virus hypothesis and has coexisted 'with it, despite
the rising popularity of the HIV hypothesis (see Sec-
tion 3).
The infectious and non-infectious AIDS hypothe-
ses indicate entirely different strategies of AIDS pre-
vention and therapy. Here we analyze the cause
of hemophilia-AIDS in the lights of the HIV-AIDS
hypothesis and the foreign-protein-AIDS hypothesis.
The hemophiliacs provide the most accessible group
to test AIDS hypotheses of infectious versus non-
infectious causation. This is because the time of infec-
tion via transfusion can be estimated more accurately
than HIV infection from sexual contacts, and because
the role of treatment-related AIDS risks can be con-
trolled and quantitated much more readily than AIDS
risks due to the consumption of illicit, recreational
drugs.
2. The HIV-AIDS hypothesis
The HIV hypothesis claims that AIDS began to appear
in hemophiliacs in 1981 (Centers for Disease Con-
trol, 1982) because (i) hemophiliacs were accidentally
infected via transfusions of factor VIII contaminat-
ed with HIV since the 1960s, when widespread pro-
phylactic factor VIII treatment began (but no longer
after 1984 when HIV was eliminated from the blood
supply) and because (ii) AIDS is currently assumed
to follow HIV infection on average only after 10
years (Centers for Disease Control, 1986; Institute of
Medicine, 1988; Chorba et at., 1994). Indeed, about
15,000 of the 20,000 American hemophiliacs, or 75%,
are HIV antibody-positive from transfusions of HIV-
contaminated clotting factors received before HIV was
detectable (Tsoukas etal., 1984; Institute of Medicine
and National Academy of Sciences, 1986; Sullivan et
at., 1986; McGrady, Jason & Evatt, 1987; Institute
of Medicine, 1988; Koerper, 1989). Contamination of
factor VIII with HIV reflects the practice, developed in
the 1960s and 1970s, of preparing factor VIII and other
clotting factors from blood pools collected from large
numbers of donors (Aronson, 1983; Koerper, 1989;
Chorbaetal., 1994).

The HIV hypothesis claims that 2,214 Ameri-
can hemophiliacs developed AIDS-defining diseases
between 1982 and the end of 1992 because of HIV
(Centers for Disease Control, 1993). However, this
corresponds only to a 1.3% annual AIDS risk, i.e. 201
cases per 15,000 HIV-positive hemophiliacs per year.
(Note that the non-age adjusted annual mortality of an
American with a life expectancy of 80 years is 1.2%).
Further, the HIV-AIDS hypothesis claims that the mor-
tality of hemophiliacs has increased over 2-fold in the
3-year period from 1987 to 1989 compared to peri-
ods from 1968 to 1986, although infection with HIV
via transfusions had already been halted with the HIV-
antibody test in 1984 (Chorba et at., 1994).
HIV is thought to cause immunodeficiency by
killing T-cells, but paradoxically only after the virus
has been neutralized by antiviral immunity, and only on
average 10 years after infection (Institute of Medicine,
1988; Duesberg, 1992a; Weiss, 1993). However, HIV,
like all other retroviruses, does not kill T-cells or any
other cells in vitro; in fact, it is mass-produced for the
HIV antibody test in immortal T-cell lines (Duesberg,
1992a). Moreover, the basis for the lO-year latent
period of the virus, which has a generation time of
only 24-48 h, is entirely unknown (Duesberg, 1992a;
Weiss, 1993; Fields, 1994). It is particularly paradox-
ical that the loss of T-cells in hemophiliacs over time
does not correspond to viral activity and abundance.
No T-cells are lost prior to antiviral immunity, when
the virus is most active (Duesberg, 1993a; Piatak et
al., 1993). Instead, most T-cells are lost when the virus
is least active or latent in hemophiliacs (Phillips et at.,
1994a) and other risk grous (Duesberg, 1992a; 1993a,
1994; Piatak et at., 1993; Sheppard, Ascher & Krowka,
1993), namely after it is neutralized by antiviral immu-
nity (a positive HIV-antibody test). Indeed, there are
healthy, HIV-antibody positive persons in which 33 to
43 times more cells are infected by latent HIV than in
AIDS patients (Simmonds et at., 1990; Bagasra et at.,
1992; Duesberg, 1994). Even Gallo, who claims cred-
it for the HIV-AIDS hypothesis (Gallo et at., 1984),
has recently acknowledge: 'I think that if HIV is not
being expressed and not reforming virus and repli-
cating, the virus is a dud, and won't be causing the
disease ... nobody is saying that indirect control of the
virus is not important ... ' (Jones, 1994).
There is also no explanation for the profound para-
doxes that AIDS occurs only after HIV is neutralized
and that antiviral immunity does not protect against
AIDS, although this immunity is so effective that
free virus is very rarely detectable in AIDS patients
51
(Duesberg, 1990, 1992a, 1993a; Piatak et at., 1993).
The high efficiency of this antiviral immunity is the rea-
son that leading AIDS researchers had notorious dif-
ficulties in isolating HIV from AIDS patients (Weiss,
1991; Cohen, 1993).
All of the above associations between HIV and
AIDS support the hypothesis that HIV is a passenger
virus, instead of the cause of AIDS (Duesberg, 1994).
A passenger virus differs from one that causes a disease
in three criteria:
1) The time of infection by the passenger virus is unre-
lated to the initiation of the disease. For example,
the passenger may infect 10 years prior to, or just
immediately before, initiation of the disease - just
as HIV does in AIDS.
2) The passenger virus may be active or passive dur-
ing the disease, i.e. the primary disease is not influ-
enced by the activity of the passenger virus or the
number of virus-infected cells, as is the case for
HIVinAIDS.
3) The disease may occur in the absence of the pas-
senger virus. In the case of AIDS, over 4621 HIV-
free AIDS cases have been clinically diagnosed
(Duesberg, 1993b; see also Section 4.6).
Therefore, HIV meets each of the classical criteria
of a passenger virus - exactly (Duesberg, 1994).
Moreover, since HIV is not active in most AIDS
patients, and often more active in healthy carriers than
in AIDS patients (Duesberg, 1993a, 1994; Piatak et
at., 1993), and since AIDS patients with and with-
out HIV are clinically identical (Duesberg, 1993b),
HIV is in fact only a harmless passenger virus. It is
harmless, because it does not contribute secondary dis-
eases to AIDS pathogenicity, as for example pneumo-
cystis pneumonia, candida or herpes virus do. These
microbes each cause typical AIDS-defining oppor-
tunistic infections. But HIV does not appreciably
affect the pathogenicity of AIDS as HIV-free and HIV-
positive AIDS cases are clinically indistinguishable
(Duesberg, 1993b, 1994). Likewise, there is no clin-
ical distinction between AIDS cases in which HIV is
active and those in which it is totally latent and restrict-
ed to very few cells (Duesberg, 1993a; Piatak et at.,
1993).
Thus, despite enormous efforts in-the last 10 years,
there is no rational explanation for viral pathogenesis,
and the virus-AIDS hypothesis stands unproved (Weiss
& Jaffe, 1990; Duesberg, 1992a; Weiss, 1993; Fields,
1994). Above all, the hypothesis has failed to make
any verifiable predictions, the acid test of a scientific
hypothesis. For example, the predicted explosion of
52
AIDS into the general population, or among female
prostitutes via sexual transmission of HIV, or among
health care workers treating AIDS patients via par-
enteral transmission did not occur (Duesberg, 1992a,
1994).
As yet, the hypothesis is supported only by cir-
cumstantial evidence, i.e. correlations between the
occurrence of AIDS and antibodies against HIV in
AIDS patients (Blattner, Gallo & Temin, 1988; Insti-
tute of Medicine, 1988; Weiss & Jaffe, Weiss, 1993).
However, because AIDS is defined by correlation
between diseases and antibodies against HIV (Insti-
tute of Medicine, 1988), the relevance of the correla-
tion argument for AIDS etiology has been challenged
(Duesberg, 1992a, 1993b, 1994; Thomas Jr., Mullis
& Johnson, 1994). States Mullis, at a London Sunday
Times Nobel Laureate lecture in 1994, 'Any postgradu-
ate student who had written a convincing paper demon-
strating that HIV 'causes' AIDS would ... have pub-
lished 'the paper of the century' . (Dickson, 1994).
In view of the circularity of the correlation argu-
ment, the apparent transmision of AIDS to hemophili-
acs via transfusion of HI V-infected blood or factor VIII
has been cited as the most direct support for the virus-
AIDS hypothesis (Blattner, Gallo & Temin, 1988;
Institute of Medicine, 1988; Weiss & Jaffe, 1990;
Weiss, 1993). However, the HIV-hemophilia-AIDS
hypothesis is weakened by the extremely long inter-
vals between infection and AIDS, averaging between
10 years (Institute of Medicine, 1988) and 35 years,
(Duesberg, 1992a; Phillips et at., 1994b) compared
to the short generation time of HIV which is only 24
to 48 h (see Section 4.2). During such long intervals
other risk factors could have caused AIDS diseases,
particularly in hemophiliacs who depend on regular
transfusions of clotting factors for survival. The fact
that HIV is typically not more active, and often even
less active, in those who develop AIDS than in those
who are healthy, further weakens the HIV-hemophilia-
AIDS hypothesis (see above).
3. The foreign-protein-hemophilia-AIDS
hypothesis
Before the introduction of the HIV-AIDS hypothe-
sis, but after the introduction of prophylactic long-
term treatment of hemophilia with blood-derived clot-
ting factors had begun, numerous hematologists had
noticed immunodeficiency and corresponding oppor-
tunistic infections in hemophiliacs. Several of these
had advanced the foreign-protein-hemophilia-AIDS
hypothesis, which holds that the long-term transfu-
sion of foreign proteins contaminating commercial fac-
tor VIII, and possibly factor VIII itself, is the cause
of immunosuppression in hemophiliacs. Indeed, until
recently most commercial preparations of factor VIII
contained from 99% to 99.9% foreign, non-factor VIII
proteins (Brettier & Levine, 1989; Mannucci et at.,
1992; Seremetis et at., 1993; Gjerset et at., 1994).
According to the foreign-protein hypothesis immun-
odeficiency in hemophilia patients is proportional to
the lifetime dose of foreign proteins received (Meni-
tove et at., 1983; Madhok et at., 1986; Schulman,
1991).
Long before HIV had been discovered, it was
known empirically that 'transfusion of patients under-
going renal transplantation is associated with improved
graft survi val and it has been suggested that transfusion
is immunosuppressive in an as yet unidentified way'.
(Jones et at., 1983). The authors had cited this empiri-
cal knowledge to explain immunosuppression in eight,
and Pneumocystis pneumonia in six British hemophil-
iacs (Jones et at., 1983). A multicenter study inves-
tigating the immune systems of 1,551 hemophiliacs,
treated with factor VIII from 1975 to 1979, document-
ed lymphocytopenia in 9.3% and thrombocytopenia in
5% (Eyster et al., 1985). Further, the CDC reported
AIDS-defining opportunistic infections in hemophil-
iacs between 1968 and 1979, including 60% pneu-
monias and 20% tuberculosis (Johnson et at., 1985).
An American hematologist commented on such oppor-
tunistic infections in hemophiliacs, including two can-
didiasis and 66 pneumonia deaths that had occurred
between 1968 and 1979, ' ... it seems possible that
many of the unspecified pneumonias in hemophiliacs
in the past would be classified today as AIDS' (Aron-
son, 1983).
In 1983, Gordon from the National Institutes of
Health noted that all hemophiliacs with immunodefi-
ciency identified by the CDC had received factor VIII
concentrate. While acknowledging the possibility of
a 'transmissible agent', Gordon argued that 'repeated
administration of factor VIII concentrate from many
varied donors induces a mild disorder of immune dis-
regulation by purely immunological means, without
the intervention of infection' . (Gordon, 1983). Froebel
et at. also argued against the hypothesis that immun-
odeficiency in American hemophiliacs was due to a
virus, and suggested that it was due to treatments with
factor VIII because 'Scottish patients with hemophil-
ia, most of whom had received no American factor

VIII concentrate for over two years, were found to
have immunological abnormalities similar to those in
their American counterparts ... ' (Froebel et at., 1983).
Already in 1983 Menitove et at. described a correla-
tion between immunosuppression of hemophiliacs and
the amount of factor VIII received over a lifetime;
the more factor a hemophiliac had received the lower
was his T4ff8-cell ratio. Their data were found to be
'consistent with the possibility that commercially pre-
pared lyophilized factor VIII concentrates can induce
an AIDS-like picture ... ' (Menitove et at., 1983). Also
in 1983, Kessler et at. proposed that' Repeated expo-
sure to many blood products can be associated with
developmentofT4/T8 abnormalities' and 'significant-
ly reduced mean T4ff8 ratios compared with age and
sex-matched controls' (Kessler et at., 1983).
After the introduction of the HIV-AIDS hypothesis
in 1984, Ludlam et at. studied immunodeficiency in
HIV-positive and HIV-negative hemophiliacs and pro-
posed 'that the abnormalities [low T4 to T8 cell ratios]
result from transfusion of foreign proteins' (Carr et at.,
1984). Likewise, Tsoukas et at. concluded 'These data
suggest that another factor, or factors, instead of, or in
addition to, exposure to HTLV-III [old term for HIV]
is required for the development of immunedysfunction
in hemophiliacs' (Tsoukos et at., 1984).
In 1985 even the retrovirologist Weiss reported
'the abnormal T-Iymphocyte subsets are a result of
the intravenous infusion of factor VIII concentrates
per se, not HTLV-III infection' (Ludlam et at., 1985).
Likewise, the hematologists Pollack et at. deduced
that, 'Derangement of immune function in hemophil-
iacs results from transfusion of foreign proteins or a
ubiquitious virus rather than contracting AIDS infec-
tious agent' (Pollack et at., 1985). The 'AIDS infec-
tious agent' was a reference to HIV, because in 1985
HIV was extermely rare in blood concentrates out-
side the U.S., but immunodeficiency was observed in
Israeli, Scottish, and American hemophiliacs (Pollack
et at., 1985). A French AIDS-hemophilia group also
observed ' ... allogenic or altered proteins present in
factor VIII ... seem to play a role of immunocom-
promising agents'. They stated that 'A correlation
between treatment intensity and immunologic distur-
bances was found in patients infused with factor VIII
preparations, irrespective of their positive or negative
LAV [HIV] antibody status' (AIDS-HemohiliaFrench
Study Group, 1985). Likewise, Hollan et at. reported
in 1985 'an immunodeficiency independent of HTLV-
III infection' in Hungarian hemophiliacs (Hollan etat.,
1985).
53
In 1986, Madhok et at. arrived at the conclu-
sion that 'clotting factor concentrate impairs the cell
mediated immune response to a new antigen in the
absence of infection with HIV' (Madhok et at., 1986).
Moreover, Jason et at. from the CDC observed that
'Hemophiliacs with immune abnormalities may not
necessarily be infected with HTLV-IIIILAV, since fac-
tor concentrate itself may be immune suppressive even
when produced from a population of donors not at
risk for AIDS' (Jason et at., 1986). Sullivan et at.
deduced from a comprehensive study of hemophiliacs
that 'hemophiliacs receiving commercial factor VIII
concentrate experience several stepwise incremental
insults to the immune system: alloantigens in factor
VIII concentrate [etc.] ... ' (Sullivan et at., 1986).
In 1987, Sh!lfP et at. commented that 'Five out of
12 such patients had a mild T4 lymphocytopenia, and
this may have been related to parenteral administration
of large quantities of protein' . (Sharp et at., 1987). And
Aledort observed that 'chronic recipients ... of factor
VIII, factor IX and pooled products ... demonstrated
significant T-cell abnormalities regardless of the pres-
ence of HIV antibody' (Aledort, 1988). Brettler and
Levine proposed in 1989 that 'Factor concentrate itself,
perhaps secondary to the large amount of foreign-
protein present, may cause alterations in the immune
systems of hemophiliac patients' (Brettler & Levine,
1989). And even Stehr-Green et at. from the CDC
conceded that foreign proteins were at least a cofactor
of HIV in immunosuppression: 'Repeated exposure to
factor concentrate ... could also account for more rapid
progression of HIV infection with age'. (Stehr-Green
et at., 1989).
Although Becherer et at. claimed in 1990 that
clotting factor does not cause immunodeficiency,
they showed that immunodeficiency in hemophiliacs
increases with both the age and the cumulative dose of
clotting factor received during a lifetime (Becherer et
at., 1990). Likewise, Simmonds et at. observed in 1991
that even among HIV-positive hemophiliacs 'The rate
of disease progression, as assessed by the appearance
or not of AIDS symptoms or signs within five years
of seroconversion, was related ... to the concentration
of total plasma IgM before exposure to infection ... '
(Simmonds et at., 1991). The hematologist Prince
noted in a review from 1992 that 'When serum sam-
ples from these [immunodeficient hemophilia] patients
were tested for antibodies to HIV-l, it was found
that a sizable group of hemophilia patients, usual-
ly 25% to 40%, were seronegative for HIV-l', and
' ... all found marked anergy, lack of response, in HIV-
54
seronegative concentrate recipients. Taken together,
these findings were interpreted as evidence that clot-
ting factor concentrates suppressed the immunocom-
petence of recipients ... ' (Prince, 1992).
In 1991, Schulman concluded that "immunosup-
pressive components in F VIII concentrates" cause
immunodeficiency not only in HIV-positive but also in
HIV-negative hemophiliacs (Schulman, 1991). Schul-
man had observed reversal of immunodeficiency and
thrombocytopenia in HIV-positi ve hemophiliacs treat-
ed with purified factor VIII, and that immunity "was
inversely correlated with the annual amount of factor
VIII infused" (Schulman, 1991).
At the same time several groups have reported that
T-cell counts are stabilized, or even increased in HIV-
positive hemophiliacs treated with factor VIII free of
foreign proteins (de Biasi et ai., 1991; Hilgartner et ai.,
1993; Seremetis et ai., 1993; Goedert et ai., 1994) (see
also Section 4.7). And in 1994, the editor of aids News,
published by the Hemophilia Council of California,
granted foreign proteins the role of a cofactor of HIV in
hemophilia AIDS with an editorial "Factor concentrate
is a Co-factor" (Maynard, 1994).
According to the foreign-protein hypothesis, anti-
bodies against HIV and against other microbes would
merely be markers of the multiplicity of transfusions
received (Evatt et aI., 1984; Pollack et ai., 1985;
Brettler et aI., 1986; Sullivan et ai., 1986; Koerp-
er, 1989). Since HIV has been a rare contaminant of
blood products, even before 1984, only those who have
received many transfusions would become infected.
The more immunosuppressive transfusions a person
has received, the more likely that person is to become
infected by HIV and other microbes contaminating fac-
tor VIII (see Section 4.6). For example, only 30% of
hemophiliacs who had received less than 400 units fac-
tor VIII per kg per year were HIV-positive, but 80%
of those who had received about 1000 units, and 93%
of those who had received over 2100 units per kg per
year were HIV-positive (Sullivan et ai., 1986).
4. Predictions of the foreign-protein- and
HIV-AIDS hypotheses
Here we compare the HIV- and the foreign-protein-
AIDS hypotheses in terms of how well their predic-
tions can be reconciled with hemophilia-AIDS:
4.1 Mortality of hemophiliacs with and without HIV
The virus-AIDS hypothesis predicts that the mortal-
ity of HIV-positive hemophiliacs will be higher than
that of matched HIV-free counterparts. Considering the
high, 75%-rate of infection of American hemophiliacs
by HIV since 1984, one would expect that the median
age of all American hemophiliacs would have signifi-
cantly decreased and that their mortality increased. The
HIV-AIDS hypothesis predicts that in 1994, at least one
lO-year-Iatent-period after most American hemophil-
iacs were infected, over 50% of the 15,000 HIV-
positive American hemophiliacs would have devel-
oped AIDS or died from AIDS (Institute of Medicine,
1988; Duesberg, 1992a). But despite the many claims
that HIV causes AIDS in hemophiliacs (Centers for
Disease Control, 1986; Institute of Medicine, 1988;
Weiss & Jaffe, 1990; Chorba et at., 1994), there is not
a single controlled study showing that the morbidity or
mortality of HIV-positive hemophiliacs is higher than
that of HIV-negative controls matched for the lifetime
consumption of factor VIII.
Instead, the mortality of American hemophiliacs
has decreased and their median age has increased since
75% were infected by HIY. The median age of Ameri-
can hemophiliacs has increased from 11 years in 1972,
to 20 years in 1982, to 25 years in 1986, and to 27 years
in 1987, although 75% had become HIV antibody-
positive prior to 1984 (Institue of Medicine and Nation-
al Academy of Sciences, 1986; Koerper, 1989; Stehr-
Green et at., 1989). Likewise, their median age at death
has increased from about 40 to 55 years in the period
from 1968 to 1986 (Chorba et ai., 1994).
Contrary to the HIV-AIDS hypothesis, one could
make a logical argument that HIV, instead of decreas-
ing the life span of hemophiliacs, has in fact increased
it. A more plausible argument suggests that the life
span of American hemophiliacs has increased as a con-
sequence of the widespread use of factor VIII that start-
ed in the late 1960s (see above). As predicted by the
foreign-protein hypothesis, the price for the extended
life span of hemophiliacs by treatment with commer-
cial factor VIII was immunosuppression due to the
long-term parenteral administration of large quantities
of foreign protein (see Section 4.2). Prior to factor VIII
therapy, most hemophiliacs died as adolescents from
internal bleeding (Koerper, 1989).
However, a recent CDC study reports that the mor-
tality of American hemophiliacs suddenly increased
2.5-fold in the period from 1987 to 1989, after it had
remained almost constant in the period from 1968 to
1986 (Chorbaet at., 1994). Since American hemophil-
iacs became gradually infected via the introduction
in the 1960s of pooled factor VIII treatments until

1984, when HIV was eliminated from the blood supply
(see above), one would have expected first a gradual
increase in hemophilia mortality and then a rather steep
decrease. The increase in mortality would have fol-
lowed the increase of infections with a lag defined by
the time that HIV is thought to require to cause AIDS.
The presumed lag between HIV and AIDS has been
estimated at 10 months by the CDC in 1984 (Auerbach
et al., 1984) and at 10 years by a committee of HIV
researchers, including some from the CDC, in 1988
(Institute of Medicine, 1988). Therefore the sudden
increase in hemophilia deaths in 1987 is not compati-
ble with HIV-mediated mortality. Hemophilia mortal-
ity should have gradually decreased after 1984, when
HIV was eliminated from the blood supply, depending
on the lag period assumed between infection and AIDS.
Even if the lag period from HIV to AIDS were 10 years,
the mortality of hemophiliacs should have significant-
ly decreased by 1989,5 years after new infections had
been stopped.
An obvious explanation for the chronological
inconsistency between infection of hemophiliacs with
HIV since the 1960s and the sudden increase in their
mortality 20 years later is the introduction of the cyto-
toxic DNA chain terminator AZT as an anti-HIV drug
in 1987. AZT has been recommended and prescribed
to symptomatic HIV carriers since 1987 (Fischl et al.,
1987; Richman et at., 1987) and to healthy HIV car-
riers with lower than 500 T-cells since 1988 (Volberd-
ing et at., 1990; Goldsmith et al., 1991; Phillips et
al., 1994b). Approximately 200,000 HIV antibody-
positives with and without AIDS diseases are cur-
rently prescribed AZT worldwide (Duesberg, 1992a).
According to a preliminary survey of hemophiliacs
from a national group, Concerned Hemophiliacs Act-
ing for Peer Strenght (CHAPS), 35 out of 35 HIV- pos-
itive hemophiliacs asked had taken AZT, and 20 out
of 35 who had taken AZT at some time were current-
lyon AZT (personal communication, Brent Runyon,
executive director of CHAPS, Wilmington, N.C.).
The DNA chain terminator AZT was developed
30 years ago to kill growing human cells for can-
cer chemotherapy. Because of its intended toxicity,
chemotherapy is typically applied for very limited peri-
ods of time, i.e. weeks or months, but AZT is now pre-
scribed to healthy HIV-positives indefinitely, despite
its known toxicity (Nussbaum, 1990; Volberding et
at., 1990). Indeed, AZT has been shown to be toxic
in HIV-positives and proposed as a possible cause of
AIDS diseases since 1991 (Duesberg, 1991, 1992c,
1992a, 1992b). Recently, the European'Concorde tri-
55
al' (Seligmann et al., 1994) and several other studies
have shown that, contrary to earlier claims, AZT does
not prevent AIDS (Oddone et al., 1993; Tokars et al.,
1993; Lenderking et al., 1994; Lundgren et al., 1994).
The Concorde trial even showed that the mortality
of healthy, AZT-treated HIV-carriers was 25% high-
er than that of placebo-treated controls (Seligmann et
al., 1994). Likewise, an American multicenter study
showed that the death risk of hemophiliacs treated with
AZT was 2.4 times higher, and that their AIDS risk
was even 4.5 times higher than that of untreated HIV-
positive hemophiliacs (Goedert et al., 1994). Thus, the
widespread use of AZT in HIV-positives could be the
reason for the sudden increase in hemophilia mortality
since 1987.
The AZT-hemophilia-AIDS hypothesis and the
foreign-protein-AIDS hypothesis both predict that
hemophilia-AIDS would stay constant or increase as
long as unpurified factor VIII is used and AZT is pre-
scribed to HIV-positive hemophiliacs. By contrast,
the HIV-AIDS hypothesis predicts that hemophilia-
AIDS should have decreased with time since 1984
when HIV was eliminated from the blood supply. The
HIV hypothesis further predicts that AIDS should have
decreased precipitously since 1989 when AZTwas pre-
scribed as AIDS prevention to inhibit HIY.
But the decrease in hemophilia-AIDS predict-
ed by the HIV-AIDS hypothesis was not observed.
Instead, the data confirm the AZT-/foreign-protein-
AIDS hypotheses: The CDC reports 300 hemophilia
AIDS cases in 1988,295 in 1989,320 in 1990,316 in
1991 , 316 in 1992 and, after broadening the AIDS def-
inition as of January 1993 (Centers for Disease Control
and Prevention, 1992), 1096 in 1993 (Centers for Dis-
ease Control, 1993; Centers for Disease Control and
Prevention, 1994; and prior HNIAIDS Surveillance
reports).
4.2 Annual AIDS risk of HIV-positive hemophiliacs
compared to other HIV-positive AIDS risk groups. The
HIV-AIDS hypothesis predicts that the annual risk of
HIV-positive hemophiliacs would be the same as that
of other HIV-infected risk groups. One could in fact
argue that it should be higher, because the health of
hemophiliacs is compromised compared to AIDS risk
groups without congenital health deficiencies.
By contrast, the foreign-protein-AIDS hypothesis
makes no clear prediction about the annual AIDS risk
of hemophiliacs compared to drug-AIDS risk groups,
because the relative risks have not been studied and are
hard to quantitate.
56
By the end of 1992, 2,214 American hemophiliacs
with AIDS were reported to the CDC (Centers for Dis-
ease Control, 1993; Chorba et al., 1994). Since there
are about 15,000 HIV-positive American hemophili-
acs, an average of only 1.3% (201 out of 15,000) have
developed AIDS annually between 1981 and 1992
(Tsoukas et at., 1984; Hardy et al., 1985; Institute of
Medicine and National Academy of Sciences, 1986;
Sullivan et at., 1986; Stehr-Green et al., 1988; Goed-
ert et al., 1989; Koerper, 1989; Morgan, Curran &
Berkelman, 1990; Gomperts, De Biasi & De Vreker,
1992). But after the inclusion of further diseases into
the AIDS syndrome (Institute of Medicine, 1988), and
the introduction of AZT as an anti-HIV drug, both in
1987, the annual AIDS risk of American hemophiliacs
appears to have stabilized at 2%, e.g. about 300 out of
15,000 per year until 1993 when the AIDS definition
was changed again (Centers for Disease Control, 1993)
(see Section 4.1).
Hemophilia-AIDS statistics from Germany are
compatible with American counterparts: about 50%
of the 6,000 German hemophiliacs are HIV-positive
(Koerper, 1989). Only 37 or ~ 1% of these devel-
oped AIDS-defining diseases during 1991 (Leonhard,
1992), and 186 or 1.5% annually during the four years
from 1988 to 1991 (Schwartlaender et al., 1992).
The 1.3% to 2% annual AIDS risk indicates that the
average HIV-positive hemophiliac would have to wait
for 25 to 35 years to develop AIDS diseases from HIV.
Indeed latent periods of over 20 years have just been
calculated for HIV-positive hemophiliacs based on the
loss of T-cells over time (Phillips et at., 1994b).
By contrast, the annual AIDS risk of the average,
HIV-positive American is currently 6%, because there
are now about 60,000 annual AIDS cases (Centers
for Disease Control, 1993) per 1 million HIV-positive
Americans (Curran et aI., 1985; Centers for Disease
Control, 1992b; Duesberg, 1992a). This reflects the
annual AIDS-risks of the major risk groups, the male
homosexuals and intravenous drug users who make
up about 93% of all American AIDS patients (Centers
for Disease Control, 1993). The annual AIDS risks of
intravenous drug users (Lemp et al., 1990) and male
homosexuals appear to be the same, as both were esti-
mated at about 5-6% (Anderson & May, 1988; Lui et
aI., 1988; Lemp et al., 1990) (Table 1).
In view of the compromised health of hemophili-
acs, it is surprising that the annual AIDS risk of HIV-
infected hemophiliacs is only 1.3% to 2% and thus 3-5
times lower than that of the average HIV-infected, non-
hemophiliac American or European (Table 1). Com-
menting on the relatively low annual AIDS risk of
hemophiliacs compared to that of homosexuals, the
hematologists Sullivan et al. noted that 'The reasons
for this difference remain unclear' (Sullivan et at.,
1986). Hardy et al. from the CDC also noted the dis-
crepancy in the latent periods of different risk groups.
"The magnitude of some of the differences in rates is
so great that even gross errors in denomination esti-
mates can be overcome" (Hardy et at., 1985). And
Christine Lee, senior author of the study that had esti-
mated latent periods of over 20 years from infection to
hemophilia AIDS (Phillips et al., 1994b), commented
on the paradox "It may be that hemophiliacs have got
that cofactor [of foreign blood contaminants], homo-
sexuals have got another cofactor, drug users have got
another cofactor, and they all have the same effect, so
that at the end of the day you get [approximately] the
same progression rate." (Jones, 1994).
Thus, the 3-5-fold difference between the annual
AIDS risks of HIV-positive hemophiliacs and the oth-
er major risk groups is not compatible with the HIV
hypothesis. However, it can be reconciled with the
foreign-protein and drug-AIDS hypothesis (Duesberg,
1992a, 1994), because different causes, i.e. drugs and
foreign proteins, generate AIDS diseases at different
rates.
4.3 The age bias of hemophilia-AIDS. The HIV-AIDS
hypothesis predicts that the annual AIDS risks of
HIV-positive hemophiliacs is independent of their age,
because virus replication is independent of the age of
the host. Predictions would have to be adjusted, how-
ever, by the hypothetical lag period between infection
and AIDS. If the average latent period from HIV to
AIDS is 10 months, as was postulated in 1984 (Auer-
bach et aI., 1984), less than 10-month-old HIV-positive
hemophiliacs would have a lower probability of having
AIDS. If the average latent period from HIV to AIDS
is 10 years (Institute of Medicine, 1988; Lui et aI.,
1988; Lemp et aI., 1990; Weiss, 1993), HIV-positive
hemophiliacs under 10 years of age would have a low-
er probability of having AIDS. In other words, if the
time of infection is unknown, the annual AIDS risks
of HIV-positive hemophiliacs over 10 months or 10
years, respectively, would be independent of the age
of the HIV-positive hemophiliac.
By contrast, the foreign-protein hypothesis predicts
that the annual AIDS risk of HIV-positive and negative
hemophiliacs increases with age because immunosup-
pression is the result of the lifetime dose of proteins
transfused (Pollack et al., 1985; Brettler et aI., 1986;

Table I. Annual AIDS risks of HIV-infected groups.
American/European risk group annual AIDS in %
Hemophiliacs 1.3-2
Male homosexuals 5-6
Intravenous drug users 5-6
Sullivan et al., 1986; Koerper, 1989) (see above). The
more years a hemophiliac has been treated with unpu-
rified blood products, the more likely he is to develop
immunodeficiency. Thus, the foreign-protein hypothe-
sis predicts that the annual AIDS risk of a hemophiliac
would increase with age.
Statistics show that the median age of hemophili-
acs with AIDS in the U.S. (Evatt et aI., 1984; Koerper,
1989; Stehr-Green et ai., 1989) and other countries
(Darby et aI., 1989; Biggar and the International Reg-
istry of Seroconverters, 1990; Blattner, 1991) is about
5-15 years higher than the average age of hemophil-
iacs. In the U.S., the average age of hemophiliacs
was 20-27 years from 1980 to 1986, while that of
hemophiliacs with AIDS was 32-35 years (Evatt et al.,
1984; Koerper, 1989; Stehr-Green et at., 1989).
Likewise, the annual AIDS risk of HIV-positive
hemophiliacs shows a strong age bias. An internation-
al study estimated the annual AIDS risk of children
at 1% and that of adult hemophiliacs at 3% over a
5-year period of HIV-infection (Biggar and the Inter-
national Registry of Seroconverters, 1990). In the U.S.,
Goedert et al. reported that the annual AIDS risk of I-
to 17- year-old hemophiliacs was l.5%, that of 18-
and 34-year-old hemohiliacs was 3%, and that of 64-
year-old hemophiliacs was 5% (Goedert et aI., 1989).
Goldsmith et al. reported that the annual T-cell loss
of hemophiliacs under 25 years was 9.5% and for
hemophiliacs over 25 years 17.5% (Goldsmith et ai.,
1991).
Lee et ai. reported that the annual AIDS risk of
hemophiliacs 11 years after HIV seroconversion was
31 % under 25 years and 56% over 25 years (Lee et
aI., /991). They estimated that the relative risk of
AIDS increased 5-fold over 25 years. The same group
confirmed in 1994 that the annual AIDS risk of HIV-
positive hemophiliacs over 30 years is 2-times high-
er than in those under 15 years of age (Phillips et
ai., 1994b). Stehr-Green et ai. estimated that ' ... the
57
References
see text
(Lui et aI., 1988), (Anderson &
May, 1988), (Lemp etal., 1990)
(Lui et al., 1988), (Anderson &
May, 1988), (Lemp et al., 1990)
risk of AIDS increased two fold for each 10 year
increase in age after controlling for year of seroconver-
sion'. (Stehr-Green et at., 1989). Likewise, Fletcher
et ai. reported a 4-fold higher incidence of AIDS in
hemophiliacs over 25 years of age than in those aged
5 to 13 years (Fletcher et ai., 1992). Thus, the annual
AIDS risk of hemophiliacs increases about 2-fold for
each lO-year increase in age.
This confirms the foreign-protein hypothesis,
which holds that the cumulative dose of transfusions
received is the cause of AIDS-defining diseases among
hemophiliacs. According to the hematologist Koerper,
'this may reflect lifetime exposure to a greater number
of units of concentrate ... " and to Evatt et ai., 'This
age bias may be due to differences in duration of expo-
sure to blood products ... ' (Evatt et aI., 1984; Koerp-
er, 1989). A recent study of HIV-free hemophiliacs is
directly compatible with the foreign-protein hypothe-
sis. The study showed that despite the absence of HIV
'with increasing age, numbers of CD4 +CD45RA +
cells decreased and continued to do so throughout life'
(Fletcher et ai., 1992).
By contrast, AIDS caused by an autonomous infec-
tious pathogen would be independent of the age of
the recipient because the replication cycle of viruses,
including HIV, is independent of the age of the host.
Thus the foreign-protein-AIDS hypothesis, rather than
the HIV-AIDS hypothesis, correctly predicts the age
bias of hemophilia-AIDS.
4.4 Hemophilia-specific AIDS diseases. The 30 AIDS
diseases fall into two categories, the microbial immun-
odeficiency diseases and the non-immunodeficiency
diseases, i.e. diseases that are neither caused by,
nor consistently associated with, immunodeficiency
(Duesberg, 1992a, 1994). Based on their annual inci-
dence in America in 1992,61 % of the AIDS diseases
were microbial immunodeficiency diseases, including
pneumocystis pneumonia, candidiasis, tuberculosis,
58
etc., and 39% were non-immunodeficiency diseases,
including Kaposi's sarcoma, lymphoma, dementia, and
wasting disease (Table 2) (Centers for Disease Control,
1993).
The virus-AIDS hypothesis predicts that the prob-
ability of all HIV-infected persons to develop a giv-
en immunodeficiency or non-immunodeficiency AIDS
disease is the same and independent of the AIDS risk
group. By contrast, the hypothesis that AIDS is caused
by drugs or by foreign proteins predicts specific dis-
eases for specific causes (Duesberg, 1992a).
In America, 99% of the hemophiliacs with AIDS
have immunodeficiency diseases, of which 70% are
fungal and viral pneumonias (Evatt et aI., 1984;
Koerper, 1989; Papadopulos-Eleopulos et ai., 1994).
Only one study reports that 1% of hemophiliacs with
AIDS had Kaposi's sarcoma (Selik, Starcher & Cur-
ran, 1987). The small percentage of Kaposi's sarcoma
may be due to aphrodisiac nitrite inhalants used by
male homosexual hemophiliacs as sexual stimulants
(Haverkos & Dougherty, 1988; Duesberg, 1992a).
There are no reports of wasting disease or demen-
tia in American hemophiliacs. An English study also
reported predominantly pneumonias and other immun-
odeficiency diseases among hemophiliacs, and also
three cases of wasting syndrome (Lee et aI., 1991).
It appears that the AIDS diseases of hemophiliacs are
virtually all immunodeficiency diseases, whereas 39%
of the AIDS diseases of intravenous drug users and
male homosexuals are non-immunodeficiency diseases
(Table 2). Since AIDS diseases in hemophiliacs and
non-hemophiliacs are not the same, their causes can
also not be the same.
The almost exclusive occurrence of immunodefi-
ciency AIDS diseases among hemophiliacs is correctly
predicted by the foreign-protein-AIDS hypothesis, but
not by the HIV-AIDS hypothesis. The prediction of
the HIV hypothesis, that the distribution of immunod-
eficiency and non-immunodeficiency diseases among
hemophiliacs is the same as in the rest of the American
AIDS population, is not confirmed.
4.5 Is hemophilia-AIDS contagious? The virus-AIDS
hypothesis predicts that AIDS is contagious, because
HIV is a parenterally and sexually transmitted virus. It
predicts that hemophilia-AIDS is sexually transmissi-
ble. Indeed, AIDS researchers claim that the wives of
hemophiliacs develop AIDS from sexual transmission
of HIV (Booth, 1988; Lawrence et ai., 1990; Weiss
& Jaffe, 1990; Centers for Disease Control, 1992a,
1993). Further, the HIV-AIDS hypothesis predicts that
wives of hemophiliacs will develop the same AIDS
diseases as other risk groups.
The foreign-protein hypothesis predicts that AIDS
is not contagious and that the wives and sexual part-
ners of hemophiliacs do not contract AIDS from their
mates.
To test the hypothesis that immunodeficiency of
hemophiliacs is sexually transmissible, the T4 to T8-
cell ratios of 41 spouses and female sexual partners of
immunodeficient hemophiliacs were analyzed (Kreiss
et ai., 1984). Twenty-two of the females had rela-
tionships with hemophiliacs with T-cell ratios below
1, and 19 with hemophiliacs with ratios of 1 and
greater. The mean duration of relationships was 10
years, the mean number of sexual contacts was 111
during the previous year, and only 12% had used con-
doms (Kreiss et ai., 1984). Since the T-cell ratios of all
spouses were normal, averaging 1.68 - exactly like
those of 57 normal controls - the authors conclud-
ed that 'there is no evidence to date for heterosexu-
al or household-contact transmission of T-cell subset
abnormalities from hemophiliacs to their spouses ... '
(Kreiss et aI., 1984).
The CDC reports that between 1985 and 1992, 131
wives of American hemophiliacs were diagnosed with
unnamed AIDS diseases (Centers for Disease Control,
1993). If one considers that there have been 15,000
HIV-positive hemophiliacs in the U.S. since 1984 and
that one-third are married, then there are 5,000 wives
of HI V-positive hemophiliacs. About 16 ofthese wom-
en have developed AIDS annually during the 8 years
(131: 8) from 1985 to 1992. But these 16 annual AIDS
cases would have to be distinguished from the at least
80 wives of hemophiliacs that are expected to die per
year based on natural mortality. Considering the human
life span of about 80 years and that on average at least
1.6% of all those over 20 years of age die annually,
about 80 out of 5,000 wives over 20 would die natural-
ly per year. Thus, until controls show that among 5,000
HIV-positive wives of hemophiliacs 16 more than 80,
i.e. 96, die annually, the claim that wives of hemophil-
iacs die from sexual or other transmision of HIV is
unfounded speculation.
Moreover, it has been pointed out that all AIDS-
defining diseases of the wi ves of hemophiliacs are typ-
ically age-related opportunistic infections, including
81 % pneumonia (Lawrence et ai., 1990). Kaposi's sar-
coma, dementia, lymphoma, and wasting syndrome
are not observed in wives of hemophiliacs (Lawrence
et ai., 1990).
 59

Table 2. AIDS defining diseases in the U.S. in 1992". Table 3. Immunosuppression in HIV-negative and -positive
hemophiliacs.
Immunodeficiencies Non-immunodeficiencies
Study HIV-negative HIV-positive
42% pneumonia 20% wasting disease
17% candidiasis 9% Kaposi's sarcoma 1.) (Tsoukas et al., 1984 6/14 9/15
12% mycobacterial, 6% dementia 2.) (Carr et al., 1984) 18/53
including 3% tuberculosis 4% lymphoma 3.) (Ludlam et al., 1985) 15
8% cytomegalovirus 4.) (Moffat and Bloom, 23 23
5% toxoplasmosis 1985)
5% herpesvirus 5.) (AIDS-Hemophilia 33 55
French Study
Total =61 % Total =39% Group, 1985)
(> 61 % due to overlap) 6.) (Hollan et al., 1985) 30/104
7.) (Sullivan et al., 1986) 28 83
" = (Centers for Disease Control, 1993)
8.) (Madhok et al., 1986) 9 10
9.}(Kreiss et al., 1986) 6117 22/24
Again, the foreign-protein, but not the HN hypoth- 1O.)(GiII et al., 1986) 8/24 30/32
esis, correctly predicts the non-contagiousness of 11.) (Brettler et al., 1986) 4 38
12.)(Sharp et al., 1987) 5/12
hemophilia-AIDS. It also predicts the specific spec-
13.) (Matheson et al., 1987) 5 3
trum of AIDS diseases in wives of hemophiliacs. By
14.)(Mahir et al., 1988) 6 5
contrast, the virus-AIDS hypothesis predicts the same
15.)(Antonaci et al., 1988) 15 10
spectrum of AIDS diseases among wives of hemophil-
16.) (Aledort, 1988) 57 167
iacs as among the major risk groups (see Table 2).
17.)(Jin etal., 1989) 12 7
It appears that the virus-AIDS hypothesis is claim- 18.) (Lang et al., 1989) 24 172
ing normal morbidity and mortality of the wives of 19.) (Jason et at., 1990) 31
hemophiliacs for HN. 20.)(Becherer et al., 1990) 74 136
21.)(Smith etal., 1993) 7
4.6 Immunodeficiency in HIV-positive and -negative
hemophiliacs. The HIV hypothesis predicts that Totals 416 770
immunodeficiency is observed only in HN-positive
hemophiliacs. By contrast, the foreign-proteinhypoth- If two numbers are listed per category, the first reports immunode-
ficient and the second healthy plus immunodeficient hemophiliacs
esis predicts that immunodeficiency is a function of per study group. In most studies immunodeficiency was expressed
the lifetime dose of transfusions received, and not by the T4/T8 cell ratio, in others by anergy. In a normal immune
dependent on HN or antibodies against HN. The system the T4/T8 cell ratio is about 2. In immunodeficient persons
foreign-protein hypothesis also predicts that HIV- it is about 1 or below 1. Studies which list both HIV-positive and
negative groups indicate that mY-positives are more likely to be
positive hemophiliacs are more likely to be immuno- immunodeficient than negatives. This is because HIV is a marker
suppressed than HN-negatives because HN is a rare for the number of transfusions received, and transfusion of foreign
contaminant of blood transfusion and thus is a marker proteins causes immunodeficiency (see Sections 3 and 4.6).
for the number of transfusions received (see Section 3,
and below) (Tsoukas et at., 1984; Ludlam et at., 1985;
Kreiss et at., 1986; Sullivan et at., 1986; Koerper, transfusion of factor VIII and contaminating proteins.
1989; Fletcher et at., 1992). According to the first of Koch's postulates (Merriam-
Twenty-one studies, summarized in Table 3, have Webster, 1965), the absence of a microbe, i.e. HN,
observed 1,186 immunodeficient hemophiliacs, 416 from a disease excludes it as a possible cause of that
of whom were HN-free. Immunodeficiency in these disease. Thus, transfusion of foreign protein, not the
studies was either defined by a T4 to T8-cell ratio of presence of HN, emerges as the common denominator
about 1 or less than 1, compared to a normal ratio of 2, of all hemophiliacs with immunodeficiency.
or by other tests such as immunological anergy. Since Nevertheless, several of the controlled studies list-
immunodeficiency was observed in the absence of HIV, ed in Table 3, which compare HIV-negative to HIV-
most of the studies listed in Table 3 have concluded positive hemophiliacs, have shown that immunode-
that immunodeficiency in hemophiliacs was caused by ficiency is more often associated with HN-positives
60
than with negatives. Although some studies did not
report immunodeficiency in HIV-positives, Table 3
lists 770 HIV-positives and 416 HIV-negatives per
1,186 immunodeficient hemophiliacs. In view of this,
one could argue that HIV is one of several possible
causes of immunodeficiency.
However, some of the investigators listed in Table
3 (Tsoukas et aI., 1984; Ludlam et al., 1985; Kreiss et
aI., 1986; Madhok et aI., 1986; Sullivan et aI., 1986)
and others who have not performed controlled stud-
ies (Koerper, 1989) have proposed that HIV is just a
marker for the number of transfusions received (Sec-
tion 3). As a rare contaminant of factor VIII, HIV has
in fact been a marker for the number of transfusions
received before it was eliminated from the blood sup-
ply in 1984, just like hepatitis virus infection was a
marker of the number of transfusions received until it
was eliminated from the blood supply earlier (Anony-
mous, 1984; Koerper, 1989). According to Kreiss
et aI., 'seropositive hemophiliac subjects, on aver-
age, had been exposed to twice as much concentrate
... as seronegative[s]' (Kreiss et aI., 1986). Sullivan et
al. also reported that 'Seropositivity to LAVIHTLV-
III (HIV) was 70% for the hemophiliac population
and ... varied directly with the amount of factor VIII
received' (see Section 3) (Sullivan et al., 1986). More
recently, Schulman reported that 'a high annual con-
sumption' of factor VIII concentrate 'predisposed' to
HIV-seroconversion (Schulman, 1991), and Fletch-
er et al. described a positive 'relationship between
the amount of concentrate administered and anti-HIV
prevalence rate .. .' (Fletcher et al., 1992).
The chronology of studies investigating immunod-
eficiency in HIV-free hemophiliacs faithfully reflects
the popularity of the HIV hypothesis: the more pop-
ular the HIV hypothesis became over time the few-
er studies investigated immunodeficiency in HIV-free
hemophiliacs. Indeed, most of the controlled studies
investigating the role of HIV in immunodeficiency of
HIV-positive and matched HIV-negative hemophiliacs
were conducted before the virus hypothesis became
totally dominant in 1988 (Institute of Medicine, 1988),
namely between 1984 and 1988 (Table 3). The studies
by Jin, Cleveland and Kaufman, and Lang et aI., both
dated 1989, and the studies by Becherer et al. and by
Jason et aI., both dated 1990, all described data col-
lected before 1988 (Table 3). After 1988 the question
whether HIV-free hemophiliacs developed immunod-
eficiency became increasingly unpopular. As a result,
only a few studies have described immunodeficiency
in HIV-free hemophiliacs.
For example, Schulman reported "worrisome evi-
dence of similar immunological disturbances has been
observed, albeit to a lesser degree, in anti-HIV-
negative hemophiliacs' and that immunodeficiency in
hemophiliacs 'correlates more strongly with annual
consumption of factor concentrates than with HIV
status' (Schulman, 1991). Fletcher et al. published
a median T4fT8-cell ratio of 1.4, with a low 10-
percentile of 0.8, in a group of 154 HIV-free hemophil-
iacs, and also showed a steady decline of T-cell counts
with treatment years (Fletcher et al., 1992). Likewise,
Hassett et al. reported that 'patients with hemophilia A
without human immunodeficiency virus type 1 (HIV-l)
infection have lower CD4 + counts and CD4 + ICD8+
ratios than controls' (Hassett et al., 1993). The study
observed an average T4/T8-cell ratio of 1.47 in a group
of 307 HIV-free hemophiliacs, differing over 50 years
in age, compared to an average of 1.85 in normal con-
trols. Unlike others Hassett et al. attributed the lowered
CD4+ counts to a hemophilia-related disorder rather
than to foreign proteins, but like others they attributed
increased CD8+ counts to treatment with commercial
factor VIII. However, Fletcher et al.'s and Hassett et
al.'s practice of averaging immunodeficiency markers
of large numbers of people, differing over 50 years in
age, obscures how far the immunity of the longest, and
thus most treated cases had declined compared to cases
which have received minimal treatments.
Since the authors of these studies did not report the
life time dosage of factor VIII treatments of HIV-free
hemophiliacs, a correlation between foreign-protein
dosage and immunosuppression cannot be determined.
On the contrary, averaging immunodeficiency param-
eters of newcomers and long-term treatment recipients
obscures the relationship between the lifetime dosage
of factor VIII and immunosuppression.
Moreover, the CDC reported 7 HIV-free hemophil-
iacs with AIDS (Smith etal., 1993). This study was one
of a package that proposed to set apart HIV-free AIDS
from HIV-positive AIDS with the new term idiopathic
CD4lymphocytopenia. The goal of these studies was to
save the virus-AIDS hypothesis, despite the presence
of HIV-free AIDS (Duesberg, 1993b, 1994; Fauci,
1993). Nevertheless all of the 7 HIV-free hemophil-
iacs met one or more criteria of the CDC's clinical
AIDS definition from 1993 (Centers for Disease Con-
trol and Prevention, 1992), e.g. they all had less than
300 T-cells per microliter (range from 88 to 296), and
three also had AIDS defining diseases such as herpes
and thrombocytopenia (Smith et al., 1993).

The occurence of immunodeficiency in HIV-free
hemophiliacs demonstrates most directly that long-
term transfusion of foreign proteins contaminating fac-
tor VIII is sufficient to cause immunodeficiency in
hemophiliacs. To prove the foreign-protein hypothe-
sis it would be necessary to show that treatment of
HIV-positive hemophiliacs with pure factor VIII does
not cause immunodeficiency. It is shown below that
this is actually the case.
4.7 Stabilization, even regeneration of immunity of
HIV-positive hemophiliacs by treatment with pure fac-
tor VIII. Commercial preparations of factor VIII con-
tain between 99% and 99.9% non-factor VIII proteins
(Eyster & Nau, 1978; Brettler & Levine, 1989; Gjerset
et al., 1994; Mannucci et al., 1992; Seremetis et al.,
1993). The foreign-protein-hemophilia-AIDS hypoth-
esis predicts that long-term transfusion with commer-
cial factor VIII would be immunosuppressive, because
of the presence of contaminating proteins. Further, it
predicts that pure factor VIII, containing 100- to 1,000-
times less foreign protein per functional unit, may not
be immunosuppressive.
Several studies have recently tested whether the
impurities of factor VIII or factor VIII by itself
are immunosupressive in HIV-positive hemophiliacs.
De Biasi et ai. showed that over a period of two
years the average T-cell counts of ten HIV-positive
hemophiliacs treated with non-purified, commercial
factor VIII declined two-fold, while those of matched
HIV-positive controls treated with pure factor VIII
remained unchanged. Moreover, four out of six aner-
gic HIV-positive patients treated with purified factor
VIII recovered immunological activity (de Biasi et
aI., 1991). Goldsmith et al. also found that the T-cell
counts of 13 hemophiliacs treated with purified factor
VIII remained stable for 1.5 years (Goldsmith et aI.,
1991). Seremetis et al. have confirmed and extended
de Biasi et al. 's conclusion by establishing that the T-
cells of HIV-positive hemophiliacs were not depleted
after treatment with pure factor VIII for three years
(Seremetis et aI., 1993). Indeed, the T-cell counts of
14 out of 31 HIV-positive hemophiliacs increased up
to 25% over the three-year period of treatment with
purified factor VIII - despite infection by HIY. By
contrast, in the group treated with unpurified factor
VIII, the percentage of those with less than 200 T-cells
per J.ll increased from 7% at the beginning of the study
to 47% at the end.
Likewise Hilgartner al. reported individual increas-
es of T-cell counts of up to 50% in a group of 36 HIV-
61
positive hemophiliacs treated with purified factor VIII
whose average T-cel1 count had declined 1% during 6
months (Hilgartner et al., 1993). Goedert et al. have
also reported that ''T-cell counts fell less rapidly with
high purity products' (Goedert et al., 1994). Moreover,
Schulman observed that four HIV-positive hemophili-
acs recovered from thrombocytopenia upon treatment
with pure factor VIII for 2-3 years, and others from
CD8-related immunodeficiency upon treatment for 6
months (Schulman, 1991).
However, despite the evidence that purified factor
VIII is beneficial in maintaining or even increasing T-
cell counts, several studies testing purified factor VIII
are ambiguous about its effectiveness in preventing or
treating AIDS (Goldsmith et al., 1991; Hilgartner et
al., 1993; Gjerset et al., 1994; Goedert et al., 1994;
Phillips et al., 1994a), Some of these studies have only
tested partial1y purified, i,e, 2-10 units/mg, instead of
highly purified, i.e. 2000-3000 units/mg, factor VIII
(Gjerset et al., 1994). But each of the studies that are
ambiguous about the benefits have also treated their
patients with toxic antiviral DNA chain terminators
like AZT. Indeed the study by de Biasi et al. was
the only one that has tested purified factor VIII in the
absence of AZT. The study by Seremetis et al. initially
cal1ed for no AZT, but later allowed it anyway. Thus
in all but one study, the potential benefits of highly
purified factor VIII have been obscured by the toxicity
of AZT (see Section 5.4).
It is concluded that treatment of HIV-positive
hemophiliacs with pure factor VIII provides lasting
stabilization of immunity, and even allows regenera-
tion of lost immunity. It follows that foreign proteins,
rather than factor VIII or HIV, cause immunosuppres-
sion in HIV-positive hemophiliacs.
5. Conclusions and discussion
Four criteria of proof have been applied to distinguish
between the virus and the foreign-protein hypothe-
sis of hemophilia-AIDS: (i) correlation, (ii) function
(Koch's third postulate), (iii) predictions, (iv) thera-
py and prevention, Each of these criteria proved the
foreign-protein hypothesis valid and the HIV hypoth-
esis invalid.
5.1 Correlations between hemophilia-AIDS and the
long-term administration of foreign proteins or HIV,
Although correlation is not sufficient, it is neces-
sary to prove causation in terms of Koch's postulates
62
(Merriam-Webster, 1965). The first of Koch's postu-
lates calls for the presence of the suspected cause in
all cases of the disease, i.e. a perfect correlation; the
second calls for the isolation of the cause; and the third
for causation of the disease with the isolated causative
agent.
All hemophiliacs with immunodeficiency described
here have been subject to long-term treatment with for-
eign proteins contaminating factor VIII. This establish-
es a perfect correlation between foreign-protein trans-
fusion and hemophilia-AIDS, and fulfills Koch's first
postulate.
By contrast, a summary of 21 separate studies
showed that 416 of 1,186 immunodeficient hemophil-
iacs were HIV-free (Table 3). Since HlV does not cor-
relate well with hemophilia-AIDS, it fails Koch's first
postulate and is thus not even a plausible cause of
AIDS.
5.2 Foreign-protein hypothesis, but not HIV hypothe-
sis, meets Koch s third postulate as cause ofimmunod-
eficiency. The fact that all hemophiliacs with immun-
odeficiency had been subject to long-term treatment
with foreign proteins, and that factor VIII treatment in
the absence of foreign proteins does not cause immune
suppression, and may even revert it, provides function-
al proof for the foreign-protein hypothesis. Thus, the
foreign-protein hypothesis meets Koch's third postu-
late of causation.
Regeneration of immunity of HIV-positives by
treatment with pure factor VIII further indicates that
HIV by itself or in combination with factor VIII is not
sufficient for hemophilia-AIDS. Therefore, HIV fails
Koch's third postulate as a cause of AIDS.
5.3 Foreign-protein hypothesis correctly predicts
hemophilia-AIDS and resolves paradoxa of HIV
hypothesis. The ability to make verifiable predic-
tions is the hallmark of a correct scientific hypoth-
esis. Application of the two competing hypotheses
to hemophilia-AIDS proved that the foreign-protein
hypothesis, but not the HIV hypothesis, correctly pre-
dicts seven characteristics of hemophilia-AIDS (see
Sections 4.1--4.7):
1) The increased life span of American hemophiliacs,
despite infection of75% by HlV, due to factor VIII
treatment, that extended their lives and disseminat-
ed harmless HIV;
2) the 3-5 times lower annual AIDS risk of hemop hi 1-
iacs, compared to other AIDS risk groups;
3) the age bias of the annual AIDS risk of hemop hili-
acs, increasing 2-fold for each lO-year increase in
age;
4) the restriction of hemophilia-AIDS to immuno-
deficiency-related AIDS diseases, setting it apart
from the spectrum of AIDS diseases in other risk
groups;
5) the non-contagiousness of hemophilia-AIDS, i.e.
the absence of AIDS diseases above their normal
background in sexual partners of hemophiliacs;
6) the occurrence of immunodeficiency in HIV-free,
factor VIII-treated hemophiliacs;
7) the stabilization, even regeneration, of immuni-
ty of HIV-positive hemophiliacs upon long-term
treatment with pure factor VIII.
It follows that the foreign-protein hypothesis, but
not the HIV hypothesis, correctly predicts hemophilia-
AIDS. In addition, the foreign-protein hypothesis
resolves all remaining paradoxa of the HIV hypoth-
esis (see Section 2):
1) The failure ofHlV neutralizing antibody to protect
against AIDS - because HIV is not the cause of
AIDS.
2) The non-correlation between the loss of T celIs
and HIV activity - because foreign proteins rather
than HIV are immunotoxic.
3) The failure of HlV to kill T cells - because T ceIl
synthesis is suppressed by immunotoxic foreign
proteins.
4) The latent periods of 10 to 35 years between
HIV and hemophilia-AIDS - because the lifetime
dosage of foreign proteins, not HIV, causes AIDS.
5.4 Treatment and prevention of AIDS. The prevention
or cure of a disease, by eliminating or blocking the
suspected cause, provides empirical proof of causa-
tion.
(i) Drug-Treatment based on HIV hypothesis: On
the basis of the HIV hypothesis, AIDS has been treat-
ed since 1987 with anti-HIV drugs, such as the DNA
chain terminators AZT, ddI, etc. (Duesberg, 1992a).
The rationale of the AZT treatment is to prevent HIV
DNA synthesis at the high cost of inhibiting ceIlu-
lar DNA synthesis, the original target of AZT can-
cer chemotherapy (see above). However, not a single
AIDS patient has ever been cured with AZT. Since
1989, healthy HIV-positive hemophiliacs have also
been treated with DNA chain terminators in efforts
to prevent AIDS. But the alleged ability of AZT to
prevent AIDS has recently been discredited by several
large clinical trials (Oddone et al., 1993; Tokars et al.,

1993; Goedert et al., 1994; Lenderking et al., 1994;
Lundgren et al., 1994; Seligmann et aI., 1994). More-
over, all studies of AZT treatments have confirmed
the unavoidable cytotoxicity of DNA chain termina-
tors (Duesberg, 1992; Oddone et al., 1993; Tokars et
aI., 1993; Lenderking et al., 1994; Lundgren et al.,
1994; Seligmann et al., 1994). One study observed
a 25% increased mortality (Seligmann et al., 1994),
and another a 4.5-fold higher annual AIDS risk and a
2.4-fold higher annual death risk in AZT-treated HIV-
positive hemophiliacs compared to untreated controls
(Goedert et al., 1994).
The failure of AZT therapy to cure or prevent AIDS
indicates either that the drug is not sufficient to inhibit
HIV or that HIV is not the cause of AIDS. The lower
mortality and much lower incidence of AIDS defining
diseases among hemophiliacs not treated with AZT
compared to those treated indicates that AZT causes
AIDS-defining diseases and mortality. Thus, there is
currently no rational or empirical justification for AZT
treatment of HIV-positives with or without AIDS.
The apparent ability of AZT to cause AIDS defining
and other diseases in hemophiliacs is just one aspect
of the many roles that drugs play in the origin of AIDS
(see footnote).
(U) Treatment based on foreign-protein hypothe-
sis: In the light of the foreign-protein hypothesis,
hemophiliacs have been treated with factor VIII freed
The drug-AIDS hypothesis, which applies to most American
and European AIDS cases other than hemophiliacs (see Section 1)
(Duesberg, 1992a), also derives support either from the absence of
AIDS, or from the stabilization of, or spontaneous recovery from
AIDS conditions in HIV-positives who don't use drugs. For exam-
ple, in August 1993 there was no mortality during 1.25 years in a
group of 918 British HIV-positive homosexuals who had 'avoided
the experimental medications on offer', and chose to 'abstain from
or significantly reduce their use of recreational drugs, including alco-
hol' (Wells, 1993). Assuming a lO-year latent period from HIV to
AIDS, the virus AIDS-hypothesis would have predicted at least 115
(918/10 x 1.25) AIDS cases among 918 HIV-positives over 1.25
years. Indeed, the absence of mortality in this group over 1.25 years
corresponds to a minimal latent period from HIV to AIDS of over
1,148 (918 x 1.25) years. On July 1st 1994 there was still not a
si~gle AIDS case in this group of 918 HIV-positive homosexuals
(J. Wells, London, pers. Comm.). Further, the T-cell counts of 197
(58% of 326) HIV-positive homosexuals remained constant over 3
years, despite the presence of HIV (Detels et aI., 1988). These were
probably those in the cohort who did not use recreational drugs or
AZT. Moreover, it has been observed that the T-cells of 29% of
1,020 HIV-positive male homosexuals and intravenous drug users
even increased up to 22% per year over 2 years (Hughes et aI.,
1994). These HIV-positives belonged to the placebo arm of an AZT
trial for AIDS prevention and thus were not intoxicated by AZT. It
is probable that the 29% whose T-cells increased despite HIV may
have given up or reduced immuno suppressive recreational drug use
in the hope that AZT would work.
63
of foreign proteins. This treatment has provided lasting
stabilization of immunity in HIV-positive hemophili-
acs. Moreover, the long-term treatment of immunode-
ficient, HIV-positive hemophiliacs with purified factor
VIII has even regenerated lost immunity. Immunolog-
ical anergy has disappeared and the T-cells in HIV-
positive hemophiliacs have increased up to 25% in the
presence of pure factor VIII (see Section 4.7) (de Biasi
et al., 1991; Seremetis et al., 1993). Thus, therapeutic
benefits including AIDS prevention and even recovery
of lost immunity by omission of foreign proteins from
factor VIII lend credence to the foreign-protein-AIDS
hypothesis.
(iii) Two treatment hypotheses - and one treat-
ment dilemma: The failure to distinguish between two
alternative hypothetical AIDS causes, HIV and for-
eign proteins, has created a dilemma for contempo-
rary hemophilia treatment. For example, Goedert et
al. acknowledge that "CD4 count fell less rapidly with
high purity products" (Goedert et al., 1994). But since
they are also treating their patients with toxic AZT (see
Section 4.1), they observe that "F VIII related changes
in CD4 concentration may have little relevance to clin-
ical disease" (Goedert et at., 1994). Indeed the group
had published a rare comparison between the annual
AIDS- and death risks of hemophiliacs treated and not
treated with AZT which indicated that the AIDS risk
of AZT-treated hemophiliacs is 4.5-times and the death
risk 2.4-times higher than in untreated controls.
In order to reconcile the apparent benefits of puri-
fied factor VIII on T-cell counts with the apparent tox-
icity of simultaneous AZT treatment, they try to sepa-
rate T-cell loss from AIDS diseases. However, despite
non-immunodeficiency AIDS diseases (see Table 2,
Section 4.4), AIDS is defined as a T-cell deficiency
(Institute of Medicine and National Academy of Sci-
ences, 1986; Institute of Medicine, 1988) and dozens
of AIDS researchers have observed that 'AIDS tends
to develop only after patients' CD4lymphocyte counts
have reached low levels .. .' (Phillips et al., 1994b).
Indeed, as of January 1993 the CDC defined less than
200 T-cells per III as an AIDS disease (Centers for
Disease Control and Prevention, 1992), and sequen-
tial T-cell counts of hemophiliacs are used as a basis
to calculate their long-term survival (Phillips et al.,
1994b).
Because of their exclusive faith in the HIV-AIDS
hypothesis, readers of the study by Seremetis et at.
(Seremetis et al., 1993), which had demonstrated that
foreign proteins associated with factor VIII suppress
T-cell counts, have even proposed to .'consider the
64
use of high-purity factor VIII concentrates in non-
hemophiliac-HIV-positive patients" as a treatment for
other AIDS patients, i.e. intravenous drug users and
homosexuals. Since hemophiliacs treated with pure
factor VIII did either not develop immunodeficiency
or even recovered lost immunity, they assumed, in
view of the HIV-hypothesis, that pure factor VIII must
inhibit HIV and thus would help all AIDS patients
(Schwarz et ai., 1994).
The solution to the treatment dilemma can only
come from treatments that are each based only on
one hemophilia-AIDS hypothesis: To test the foreign-
protein hypothesis, two groups of hemophiliacs must
be compared that are matched for their life time dosage
offactor VIII, for their percentage of HIV-positives (for
their percentage and dosage of prior AZT treatment, if
applicable), and for their age. All AIDS-defining dis-
eases must be diagnosed in each group clinically for
the duration of the test. No anti-HIV treatments must
be performed. One group would be treated with puri-
fied factor VIII, the other with commercial factor VIII
contaminated with foreign proteins.
To test the HIV-AIDS hypothesis, two groups of
hemophiliacs must be compared that are matched for
their life time dosage of factor VIII treatment and their
age. The two groups must differ only in the presence
of antibody against HIY. Both groups would be treated
with the same factor VIII preparation. Only the HIV-
positive group would receive AZT. All compensatory
treatments of AZTrecipients, e.g. blood transfusions to
treat for AZT-induced anemia, neutropenia or pancy-
topenia (Richman et ai., 1987; Volberding et ai., 1990;
Duesberg, 1992), would have to be recorded. During
the duration of the test, all AIDS-defining diseases
would each be recorded clinically in both groups.
The outcome of each treatment strategy, purified
factor VIII or AZT, would be determined based on
morbidity and mortality, including AZT morbidity and
mortality, and corrected for treatments compensating
for AZT toxicity. As yet, no controlled treatment stud-
ies based on a single AIDS hypothesis have been per-
formed.
Nevertheless, the study by de Biasi et ai. (de Biasi
et at., 1991) and with reservations that by Seremetis
et al. (Seremetis et ai., 1993) come close to the stated
criteria for a test of the foreign-protein hypothesis (Sec-
tion 4.7). Seremetis et at. initially excluded, but later
allowed AZT treatment. Both studies showed that puri-
fied factor VIII improved immunodeficiency (see ii).
However, since all subjects in these studies were HIV-
positive, one could indeed argue that the improvement
of those treated with purified factor VIII was due to a
cooperation between HIV and purified factor VIII.
The definitive treatment of immunodeficiency in
hemophiliacs, or of hemophilia-AIDS, could be only
as far away as the duration of one carefully controlled
treatment test.
Acknowledgements
I thank Siggi Sachs, Russell Schoch, and Jody
Schwartz (Berkeley) for critical reviews, and Robert
Maver (Overland Park, MO), Scott Tenenbaum, Robert
Garry (Tulane University, New Orleans), Jon Cohen
(Science, Washington DC) and Michael Verney-Elliot
(MEDITEL, London) for critical information. This
investigation was supported in part by the Council
for Tobacco Research, USA, and private donations
from Tom Boulger (Redondo Beach, CA, USA), Glenn
Braswell (Los Angeles, CA, USA), Dr. Richard Fisch-
er (Annandale, VA, USA), Dr. Fabio Franchi (Trieste,
Italy), Dr. Friedrich Luft (Berlin, Germany) and Dr.
Peter Paschen (Hamburg, Germany).
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Critical analysis of the current views on the nature of AIDS
Vladimir L. Koliadin
Kharkov Aviation Institute, Kharkov, Ukraine
Received 30 March 1994 Accepted 18 July 1994
1. Introduction
During the last decade, the theory has been officially
accepted that AIDS is caused by the retrovirus called
HIV, which is transmissible through sexual contacts
and parenterally. It is widely believed that the basis of
AIDS is HIV-mediated cytotoxicity for infected CD4+
cells, which causes strong dysfunctions of the immune
system due to the depletion of CD4+ pool of lympho-
cytes; as a result, a patient dies due to one of 25-28
AIDS-associated diseases.
The official acceptance of the viral theory of AIDS
has a strong influence on the society at large, as well
as on the orientation of the research activity directed to
find some measures against AIDS. Despite the billions
of dollars that have been spent in accordance with this
theory, real positive results have not yet been achieved.
The basic tenets of the current official theory had
not been discussed and critically analyzed by the
scientific community before the theory was official-
ly announced in April 1984. By 1986 the theory
had become almost totally accepted. The first serious
arguments against the HIV/AIDS theory appeared in
1988, when P. Duesberg published an alternative view,
according to which AIDS is not an infectious disease,
and caused by some non-contagious factors, mainly
drug consumption and some other lifestyle associat-
ed factors (Duesberg, 1988). The hypothesis has been
developed in several works (Duesberg, 1991; 1992a;
1992b).
Reaction of the biomedical scientific community
to the alternative views was negative and unusually
emotional. A distinctive feature of this reaction was
the rather narrow range of factual arguments against
the new hypothesis, accomplished by lots of statements
69
unusual and unacceptable to normal scientific dispute
(see, for example, Maddox, 1993a; 1993b).
The chief aim of my paperis to analyze critically the
scientific credentials of the official theory, according
to which AIDS is caused by HIY. As an alternative
view, the core idea of Duesberg's hypothesis is being
considered: that AIDS is caused by non-contagious
lifestyle associated factors, and that HIV has no causal
role in the pathogenesis of AIDS.
Within the paper I will use two working terms
to name the two systems of views: 'viral theory' or
'HIV/AIDS theory' for the official view, and 'non-
infectious theory' for the alternative one.
The main items of the official HIV/AIDS theory,
which is under the scrutiny, may be specified as follows
(Blattner, 1991; Levy, 1989).
(1) AIDS is caused by the retrovirus called HIV;
(2) HIV causes AIDS by infection of CD4+ cells and
their killing due to a cytopathic mechanism (direct
or mediated by attack of the infected cells by the
immune system).
(3) HIV (and consequently AIDS) is transmissible
through sexual contacts;
(4) AIDS is a disease with 100% mortality;
(5) Positive results of immunological tests for antibod-
ies against some HIV proteins, or for these proteins
themselves, means the patient has HIV-infection;
(6) The symptoms of AIDS are explainable through
depletion of the CD4+ pool of lymphocytes;
(7) Main therapeutic measures against AIDS are:
(a) antiviral chemical therapy;
(b) vaccines against HIV;
(8) The main directions of future research are:
(a) investigating of the specific mechanisms by
which HIV causes AIDS;
70
(b) development of new antiviral drugs;
(c) development of vaccines capable of stimulating
immune response against HIV.
According to the adherents of the HIV/AIDS the-
ory, the main factual arguments in favor of the
HIV/AIDS theory are as follows:
(1) There is a strong correlation between HIV and
AIDS:
(a) all, or almost all, AIDS patients are reported to
be positive for HIV;
(b) AIDS and HIV are widely spread within the
same social groups, mainly homosexual or bisexual
men, and injecting drug users;
(c) geographical distribution of AIDS and HIV are
correlated;
(d) there is a statistical association between the
moment of seroconversion and fall of the CD4+
cell counts
(2) AIDS demonstrates epidemiology of an infectious
disease:
(a) geographical clusters;
(b) specific groups of the population are highly
susceptible;
(c) exponential growth of AIDS incidence.
(3) The putative CD4+ selective cytopathic mecha-
nisms of HIV action look to be persuasive and well
compatible with known facts.
This work does not pretend to create a new theory
of AIDS. The goals of this publication are to analyze
the official AIDS theory critically, to try to find obvious
gaps in our knowledge, and to propose some directions
for future research in the field of HIV and AIDS.
2. The HIV-AIDS correlation is compatible with
both rival theories
2.1 Correlation between HIV and AIDS cannot be used
to distinguish the two rival theories
The high correlation between HIV-antibody positive-
ness and AIDS is the central argument in favor of the
HIV/AIDS theory, which is widely used in the HIV-
AIDS controversy by the proponents of the official the-
ory. In the previous section four kinds of observations,
which demonstrate such a correlation, are specified. At
first sight, these facts look to be very persuasive proof
of the official view. But, despite this apparent persua-
siveness of the arguments, the viewpoint is extremely
vulnerable to criticism.
First of all, it is necessary to note that the offi-
cial statistics in AIDS and HIV are based on indirect
evidence of HIV presence - a positive HIV-antibody
test. It is obvious that, even if the positiveness is real-
ly caused by the virus (several alternative explana-
tions are described in this paper), the presence ofHIV-
antibodies does not necessarily mean that the virus is
currently present in the organism. It is quite probable
that sero-positiveness has been caused by viral infec-
tion in the past, and the organism is currently healthy
with respect to HIV. Only direct isolation of the virus
can be used as proof of HIV presence. Therefore, with-
in this paper the correlation is being discussed not for
HIV and AIDS, but for HIV-antibody positiveness and
AIDS.
It is useful to recall a basic rule well known in
applied statistics: a correlation between some two fac-
tors is not the reason to make a decision about a causal
relation between them. Moreover, attempts to draw
such a conclusion from the correlation are pointed out
in almost any course of applied statistics as a typical
logical error.
If some two factors, say A and B, are correlated,
there are at least four logically acceptable explanations
for the correlation:
(a) A is the cause of B;
(b) B is the cause of A;
(c) A and B have some general cause (a factor C);
(d) the correlation is overestimated and not significant
statistically; it can be explained by chance or by
some bias in the data gathering procedure used;
Let us assume that 'A' means positive results of a
test for HIV-antibodies, and 'B' means clinical symp-
toms of AIDS. Why should we believe that correlation
between factors A and B has to be interpreted in favor
of the causal role of the A-factor (a positive test), while
there are at least three alternative explanations?
It seems natural to consider the other two cases
('b' and 'c') as possible explanations of the A-B cor-
relation, as well as to analyze factors which lead to
the overestimation of the correlation between HIV and
AIDS.
The simplest alternative explanation of the
observed correlation between AIDS and HIV-antibody
positiveness, that fits the 'B-causes-A' case, is that
individuals whose immune systems are already com-
promised by some factors are highly susceptible to HIV
infection; these defects of the immunity then proceed to
full-blown AIDS in some of the individuals. The exper-
imental data available 'are equally consistent with the
conclusion that higher viraemia is a consequence of,

rather than the proximate cause of, defective immune
system' (Sheppard, Ascher & Krowka, 1993). Thus,
it is a plausible explanation of the correlation between
HIV-positiveness and AIDS that HIV infection is only
a sign of some dysfunctions of the immune system and,
perhaps, those of other organism's subsystems. Thus,
even being of 100% value, the HIV-AIDS correlation
cannot be a proof of the causal role of HIV in AIDS.
Let us consider the third case: 'A and B have a
general cause'. HIV-positiveness and AIDS are widely
spread in specific groups of the population: mainly
homo- and bisexuals, and injecting drug users. If some
two groups of factors are associated with the lifestyle
- one of them stimulates HIV spread, and another
includes immunosuppressive factors - the observable
HIV-AIDS correlation tends to be high.
For example, if HIV is really a transmissible agent
(the author has a strong doubt that this is really the
case), the first group of factors includes a high lev-
el of promiscuity, and common use of unsterile nee-
dles for injection; these factors result in high rates of
HIV spread. The second group offactors includes such
lifestyle associated factors compromising the immune
system as the use of recreational drugs, sexual stim-
ulants, antibiotics with a wide spectrum of action
(as a preventive measure against sexually transmit-
ted diseases), malnutrition, and some others. Thus, the
potential for virus transmission accompanied by non-
contagious immunosuppressive factors in the above
mentioned groups increases drastically, but indepen-
dently, the chances of their members to be HIV infected
and to have AIDS. In other words, although HIV and
AIDS in this case are not linked causally, a correlation
between them is observed.
A second plausible explanation of the relative-
ly high correlation between HIV-antibody positive-
ness and AIDS, fitting the (c) mechanism (A and
B are caused by a C factor), is false-positive tests
caused by common lifestyle associated factors of
AIDS-risk groups. There are experimental facts that
non-contagious factors associated with lifestyle of
AIDS-risk groups can stimulate false-positive results
of HIV-antibody tests (Papadopulos-Eleopulos, Turner
& Papadimitriou, 1993).
Taking into account compact living of the gay com-
munity members and concentration of injecting drug
users in separate places, lifestyle could explain, at least
partially, the observed geographical correlation and
clustering of the HIV-positiveness and AIDS, which
are used by the proponents of the viral theory as facts
that confirm their views.
71
Despite the claims of the adherents to the official
HIV/AIDS theory that all AIDS patients are positive
for HIV-antibodies, these claims appear to be incorrect:
there are lots of mechanisms which lead to the increase
of the observed statistical association between HIV-
antibody positiveness and AIDS. These effects may be
subdivided into two groups specified in the following
two subsections.
2.2 How a positive HIV-test can cause AIDS
The general acceptance of the official HIV/ AIDS the-
ory may lead to significant increase of AIDS risk for
HIV-positives at least in two ways. This, in turn, caus-
es an increase in the observable statistical association
between HIV-positiveness and AIDS.
2.2.1 Psychological reaction to a positive HIV-test
What is the reaction of a person who has been informed
that he or she is positive for HIV? Because of the inten-
sive propaganda of the official theory, almost every-
one thinks HIV is synonymous with AIDS and, final-
ly, with death. Thus, it is natural that in most cases
a positive HIV-test causes severe shock and depres-
sion, followed frequently by weakening of the will and
unhealthy changes in lifestyle: consumption of alco-
hol, recreational drugs, and others. It is well known
that severe psychological states are a serious factor
in compromising the immune system. Such an effect
may explain why the decrease of CD4+ cell counts is
correlated in time with the first positive HIV-antibody
test.
2.2.2 Anti-HIV therapy
A positive test for HIV, due to the general belief in the
viral nature of AIDS, leads to attempts of medical staff
to persuade the patient to receive some therapy: to use
highly toxic anti-viral drugs (AZT and others), and to
use wide-spectrum antibiotics.
The negative effect of the AZT and other anti-viral
drugs, used for treatment of HIV-positives, for the
health state at large and the immune system are well
documented. Positive effects of these drugs for pro-
longing the asymptomatic period after the first positive
test for HIV are highly controversial. Thus, a positive
result of a test for HIV for many patients results in
highly toxic anti-viral treatment. In other words, lots
of AIDS cases may be induced chemically by anti-viral
treatment (Duesberg, 1992a), and the high mortality is
due to the official acceptance of the viral theory.
72
2.3 Overestimation of the correlation
There are several approaches, mainly the way the
statistics are being collected and interpreted, which
lead to overestimates of the HIV-AIDS correlation.
2.3.1 Non-documented HIV
Because the HIVIAIDS hypothesis has been officially
accepted, AIDS and HIV-infection are considered as
synonyms. In many of the CDC reports the term AIDS
has been replaced by 'HIV-infection' or 'HIV-disease'.
On the other hand, the 1987 CDC case definition of
AIDS does not insist on a positive result of an HIV-
test. This fact creates a serious bias in data-gathering
procedures in favor of the HIV/AIDS hypothesis.
In many studies, the AIDS patients diagnosed with-
out testing for HIV are being accounted for as HIV
positive. The following citation furnishes a typical
example: 'Patients were considered to have document-
ed human immuno-deficiency virus (HIV) infection
only if they met the 1987 CDC case definition for
AIDS or were documented to be HIV seropositive'
(Frieden et al., 1993). Thus, the symptoms of AIDS
are sufficient to register the patient as HIV-positive
even if HIV-tests have not been really performed. This
is a classical logical vicious circle: HIV-positiveness is
being proved through AIDS-symptoms, and then such
pseudo-positives are used to prove correlation between
HIV and AIDS.
Finally, there are lots of registered cases of HIV-
positiveness that are not suppored by an HIV-test; it
is a logical error to use official statistics as a proof of
high HIV-AIDS correlation.
2.3.2 Elimination of AIDS cases without HIV
Almost every physician believes that AIDS is caused
by HIY. An obvious consequence of such a belief is that
a negative test for HIV reduces drastically the proba-
bility that a patient demonstrating AIDS symptoms
is correctly diagnosed as having AIDS. Because such
cases really exist, proponents of the official theory use
a new term - 'idiopathic CD4+ T-Iymphocytopenia'
- for such AIDS cases (Smith et at., 1993; Ho et al.,
1993; Spira et aI., 1993; Duncan et al., 1993).
Some consequences of the above hypothesis have
been tested by direct analysis of the United States mor-
tality trends. It has been found that the mechanism of
data bias really exists, and up to a thousand deaths from
AIDS in the USA are misclassified annually as deaths
from non-AIDS diseases (for details see Section 3).
2.3.3 Use of unmatched controls in tests for HN-
antibody specificity
Interpretation ofthe positive results ofHIV tests, espe-
cially those based on the detection of antibodies to
HIV proteins, is under the influence of the gener-
al belief in absolute or, at least, very high speci-
ficity of immunochemical reactions. Positive reac-
tion of blood serum with HIV-proteins is usually con-
sidered evidence of the presence of HIV-antibodies.
Recent studies demonstrate false positive HIV-tests
are much more frequent than has been presumed
recently, and are caused by many factors unrelated
to HIV (Papadopulos-Eleopulos, Turner & Papadim-
itriou, 1993).
Despite the wide use of HIV-antibody-test systems,
there are no quality control studies with matched con-
trol groups. Usually, healthy individuals are used as
controls. For example, US Army recruits have been
used to estimate false positive results of ELISA test-
systems (as a gold standard the Western Blot has been
used). The recruits are normally young individuals in
good health. This seems to be a violation of a basic
principle of objective biomedical study - the use of
matched controls.
In this case, the principle of matched controls
means that the negative control has to be formed using
patients with symptoms which matched with AIDS dis-
eases to the greatest extent possible - diarrhea, fever,
immuno-deficiency states (not diagnosed as AIDS) -
as well as individuals with lifestyles similar to that
of AIDS patients - recreational and aphrodisiac drug
users, homosexual men, and so on. The only way to
estimate the rate of false positive results for a test sys-
tem is to use direct virus isolation as a gold standard
of HIV infection. Until such studies have been per-
formed, any conclusion about the rate of false-positive
results is not correct, and the rate is underestimated.
How can an HIV-free organism demonstrate a
positive test for HIV-antibodies? It is necessary to
take into account that an HIV-antibody test detects
nothing but an affinity of blood serum to the pro-
teins used in the test-system, which are supposed
to belong to HIY. There are at least two phenome-
na which can lead to false-positive results: immuno-
chemical cross-reactivity, and non-specific reactivity.
For more detailed descriptions of these mechanisms,
which could result in a positive test for HIV-antibodies
without HIV actually being present, see Section 6.

2.3.4 Multiple HIV-tests among patients with AIDS
symptoms
Let us consider the situation when a physician treats a
patient with clear AIDS symptoms but with a negative
HIV test. Taking into account the belief of the physi-
cian in HIV as the cause of AIDS, it seems obvious that
his (or her) decision, with a great deal of probability,
will be to repeat the test. And such multiple testing
has really taken place (Selvey, 1993). Moreover, it is
natural that more sensitive test systems may be used
for these cases.
Such repetition of the HIV tests for patients with
AIDS symptoms, especially with the use of various
test systems, creates a bias in favor of the HIV/AIDS
hypothesis: out of two patients, the one who has some
AIDS symptoms has a greater probability of being clas-
sified as an HIV-positive.
2.3.5 Multiple CD4+ tests among HN-positives
It is a usual practice in the health monitoring of asymp-
tomatic HIV-positives to estimate their CD4+ cell
counts periodically. If the counts have occurred low-
er than the critical rates established by the CDC, an
AIDS diagnosis is attached to the patient. Taking into
account that CD4+ cell counts tend to be unstable, the
greater the number of tests, the greater the probability
of finding the counts below the critical value because
of pure chance.
On the other hand, the real diagnostic value of low
CD4+ cell counts remains unclear: there are exam-
ples of HIV-negative men with low CD4+ counts, and
cases of patients with extremely low (a few tens of
cells per microliter) or even null counts without notice-
able problems with their health. Furthermore, exten-
sive studies of the CD4+ cell counts have not been
performed for various groups of non-AIDS patients
and healthy individuals, especially those matched in
some symptoms with AIDS patients. Therefore, to use
the CD4+ cell counts as a main diagnostic criterion of
AIDS looks to be premature. This is another exam-
ple how such a basic principle of biomedical studies
as the use of matched controls has been violated in
mainstream AIDS research.
Thus, HIV-positiveness itself makes a patient like-
ly to be subjected to multiple estimation of his or her
cell counts. This, in turn, increases the probability to
be diagnosed as having AIDS if the counts are low
enough at least in one test. It is an example how the
general trust in and use of the formal clinical crite-
rion of AIDS (HIV-positiveness plus low CD4+ cell
73
counts) increases the visible correlation between HIV
and AIDS.
3. Signs of AIDS without HIV in the US mortality
trends
What are the observable consequences if the hypoth-
esis that AIDS is not caused by HIV and that there
are AIDS cases without HIV is true? One of them
is the existence of unrecognized AIDS cases: some
number of AIDS cases are likely to be unrecognized
AIDS cases: some number of AIDS cases are likely
to be unrecognized and misclassified as other diseases.
This is because, for the vast majority of physicians,
HIV and AIDS are synonymous, and a negative test
for HIV reduces the probability that a patient with
AIDS is diagnosed correctly. The aim of this study, the
results of which are described below, was to check this
hypothesis by direct analysis of mortality statistics.
Since 1987, all the deaths from AIDS have been
registered by the Centers for Disease Control with-
in the cause-of-death category 'All other infectious
and parasitic diseases' (AOIPD). The basic idea of the
study is very simple: to eliminate the cases diagnosed
as AIDS and to compare the number of remaining cas-
es with a base level in the past, when AIDS was rare or
absent. The 1980 mortality from AOIPD has been used
as the base level. Because the number of cases in 1980
for every age category was small (a few tens of deaths
per year), the mean value for the years 1979-1981 has
been used to reduce the natural statistical variation. The
source of original statistics concerning mortality from
AOIPD in 1979-1981 and 1990, and that from AIDS
in 1990 are the CDC's reports (Centers for Disease
Control, 1992; 1993b).
All the relevant quantitative information used is
summarized in Table 1. The number of deaths from
AOIPD in 1990, after the AIDS cases have been sub-
tracted, and the base level of the mortality from AOIPD
in 1979-1981, are shown in Fig. 1. Fig. 2 shows the
increase of the non-AIDS deaths from AOIPD in 1990
in respect to the base level of 1979-1981. Fig. 3 depicts
the number of deaths from AIDS in 1990.
Two peculiarities in the results are pertinent to the
question about AIDS without HIY. First, there is a
more than 4-fold increase in mortality from AOIPD
during the decade 1980-1990 in the age categories
30-44 (Fig. 1). This increase is not explainable by
AIDS because the AIDS cases are eliminated. Second-
ly, the distribution of this increase in mortality among
74

Table 1. Annual deaths from 'All other infectious and parasitic diseases' among males, USA.

Age 1980' 1990

All AIDS Non-AIDS Non-AIDS
deaths (increase since 1980)
No No No(%) No (ratio to 1980) No(%) ratio to AIDS

20-24 44 453 382 ( 1.8) 71 1.61 27 ( 2.6) 0.071

25-29 57 2754 2579 (12.0) 175 3.07 118 (11.5) 0.046
30-34 62 5111 4854 (22.6) 257 4.15 195 (19.0) 0.040
35-39 67 5607 5298 (24.7) 309 4.61 242 (23.6) 0.046
40-44 67 4268 3986 (18.6) 282 4.21 215 (20.9) 0.054
45-49 85 2557 2320 (10.8) 237 2.79 152 (14.8) 0.066
50-54 131 1424 1245 ( 5.6) 179 1.37 48 ( 4.7) 0.039
55-59 174 986 782 ( 3.6) 204 1.17 30 ( 2.9) 0.038

Total 687 23160 21446 (100) 1714 2.49 1027 (100) 0.048

'the mean value for years 1979-1981 has been used

-
Number of deaths Thousands

1980
•
soo II
1990
4

200 8

2
100

o 20-24 211-28 SO-84 811-88 40-44 411-4e 110-114 1I11-lIe

20-24 211-28 30-84 811-88 40-44 411-48 110-114 1111-118 Age group
Aoe group
Fig. 1. Annual number of deaths from 'All other infectious and Fig. 3. Annual number of deaths from AIDS registered in 1990;
parasitic diseases', not diagnosed as AIDS; males, USA. males, USA.

Increase of deaths number the different age categories is very similar to that of the
211Or---------------------------------~ AIDS deaths: despite the 14-fold variation in AIDS
deaths for different age groups within 20-54, the per-
200
centage increase of the non-AIDS deaths varies only
1110 4 to 6 percent with respect to the number of AIDS
deaths. Visual comparison of Fig. 2 with Fig. 3 also
100 demonstrates a strong similarity between the patterns
of AIDS mortality and the detected 'excessive' deaths
from AOIPD not associated with diagnosed AIDS.
Analysis of the mortality distribution patterns
o
20-24 215-:28 SO-84 811-88 40-44 411-48 110-114 114-118 within 5-year age groups for 72 causes of death
Age group (Centers for Disease Control, 1992) has shown that
Fig. 2. Increase in the annual number of the deaths from' All other the AIDS pattern is unique for AIDS and may be con-
infectious and parasitic diseases' not classified as AIDS during the sidered as its 'signature' . The strong similarity between
decade 1980-1990; males, USA.
the mortality age-patterns for 'excessive' deaths from

AOIPD having occurred in 1980-1990 and the pat-
terns of AIDS is a persuasive argument in favor of the
hypothesis that the 'excessive' deaths are caused by
the same factors that also cause AIDS.
The above mentioned results confirm the hypoth-
esis that AIDS without HIV, not diagnosed correctly
because of the negative HIV-test, is real. A thousand
of the 'excessive' (in comparison with 1980) annu-
al deaths from AOIPD in the USA, not mediated by
AIDS, appears to be only a lower boundary of the
real value of unrecognized AIDS cases, because deaths
from some AIDS-associated diseases are registered in
cause-of death categories other than AOIPD.
4. Analysis of compatibility between the putative
cytopathic mechanism of AIDS and known facts
about viral burden
A central point of the official HIV/AIDS theory is that
HIV affects the immune system through infection of
CD4+ lymphocytes, followed by the elimination of the
infected cells due to direct cytopathic effect(s) medi-
ated by the immune response. This point of the theory
is extremely vulnerable to criticism because it con-
tradicts known facts about the low levels of HIV in
HIV-positives. That is why publication of two works
(Pantaleo et al., 1993a; Embretson et al., 1993) caused
a positive resonance in the AIDS scientific community,
associated with further attacks on the alternative views
about the nature of AIDS (Maddox, 1993a).
In the two experimental works it has been stat-
ed that the HIV burden in HIV-antibody positives is
much higher than has been reported earlier, and that
HIV 'hides' in the lymphoid tissue. Two questions are
to be answered. Firstly, are the newly reported values
of viral burden really compatible with the hypothetical
cytopathic mechanism according to which HIV affects
the immune system? Secondly, are these reported val-
ues a reliable and correct interpretation of the experi-
mental facts?
4.1 Can the viral burden reported explain the observ-
able loss of CD4 + cells in AIDS patients?
What is the lower boundary of the HIV infected cells
that could explain through cytopathic mechanisms the
decrease in CD4+ cell counts that is observed in AIDS
patients? What follows are some results of a quantita-
tive analysis of the problem.
75
The simplest mathematical model for the cell infec-
tion dynamics is the pair of differential equations for
the numbers X(t) and yet) of uninfected and infected
CD4+cells:
dX/dt A - ,X - j3XY,
dY/dt j3XY - CtY;
where, is the death rate of uninfected cells, j3 is the
cell-to-cell infection rate, Ct is the death rate of infected
cells (Ct > ,), and A is the rate of production of new
cells by the immune system. To meet the assumption
of equilibrium between the cells production and their
natural death in a healthy organism (that is, if Y = 0),
we have to assume A = ,.
The question to be answered is what frequency
Finf = YI (X + Y) of the infected cells must be
observed during asymptomatic phase to explain some
given value ofthe final cells 10ssN = N/N(O) (where
N = X + Y is the total number of cells - both infected
and uninfected)? The estimates for the F inf , observed
in asymptomatic HIV-infected men, is 0.001 ... 0.01
(Pantaleo et al., 1993a; 1993b). The CD4+ cell loss in
AIDS patients is 0.1 ... 0.3 (in ratio to the initial value
N(O) in healthy individuals).
The main difficulty is the great deal of uncertain-
ty in respect to the three parameters of the model: A,
Ct, j3. To avoid this uncertainty the following method
has been used. Let us analyze not the dynamics of
cell-numbers X(t), yet) in time, but the phase por-
trait of the system in the coordinates 'relative num-
ber of cells' (N = N/N(O)) and 'fraction of infected
cells' (Y/(X + Y». Such a portrait depends only on two
parameters: the ratios AI Ct and j3 ICt. Thus, the number
of uncertain parameters has been reduced from three
to two.
Then, let us consider the extreme case, when the
regenerative power of the immune system is void:
A = O. This case is the best one for the official cyto-
pathic hypothesis. Now we have only one uncertain
parameter: the ratio j3 I Ct. In Fig. 4 a set of phase por-
traits is presented for different values of this ratio. They
have been calculated by direct numerical integration of
the above set of two differential equations.
It is easy to note from Fig. 4 that there is strong
dependency between the final cell loss, which is due to
cytopathic effect, and the maximal frequency of infect-
ed cells observed during the asymptomatic phase: the
lower the relative number NIN(O) of total cell counts
in the end of the asymptomatic phase, the greater the
fraction of infected cells that has to be observed. For
76
following method has been used. Phase portraits have
Frequency of Infected cella been calculated for several values of the 131 a ratio.
Then, for every phase portrait two values have been
0.8 estimated: maximal frequency Finf max of the infected
cells, and the minimal value N min of the total CD4+ cell
count. At the next step, this set of pairs of values has
0.4
been represented as a curve in the coordinates (Nrnin ,
Finf max). Such curves have been obtained for sever-
0.2 al values of the cell immigration rate A. The curves
are depicted in Fig. S. They make it possible to find
0.0 UUJ~----'.~..L:"""~~==:;:=:::i:: easily the frequency of infected cells which has to be
0.0 0.2 0.4 0.8 0.8 1.0 observed to explain a given value of the total cell count
Total number of cella reduction rate N min = Nmin/N(O).
Fig. 4. Phase portraits of the hypothetical HIV infection in the For example, if the final CD4+ cell count reduc-
CD4+ pool of lymphocytes in coordinates 'total number of cells' - tion rate due to HIV-mediated cytopathic mechanism
'frequency of infected cells' . The starting point is in the right-bottom
comer: the initial frequency of infected cells is 0.001. The ratio of
is 0.2 (from the initial cell count in a healthy individ-
cell-to-cell infection rate to the death rate of the infected cells is ual), the following frequency of infected cells has to
shown above the corresponding curves. be observed: 0.2S for A = 0 (the ideal case for the
cytopathic hypothesis, but not a realistic one), 0.48
for A = O.la, and so on. Thus, even under very
Maximal frequency cautious assumptions about the regenerative power of
01 Infected oeDa the immune system, the incompatibility between the
reported frequency of infected cells (upper bound is
1.0 0.001 ... 0.01) and the observable CD4+ cell loss in
I'~";:---
AIDS patients may be estimated quantitatively as 2S-
0.8 0.5 SOO-fold.
0.8
0.25
Some consequences derived from a simplified mod-
el, where the number Y of infected cells is supposed to
0.4
be constant, have been published (McLean & Michie,
0.2 0.0 1993). The assumption made is at variance with the
0.0 L - _ - - ' -_ _- ' -_ _"--_---'_ _- - ' - _ - - I experimental results (Fauci et al., 1993), as well as with
0.0 0.05 0.10 0.15 0.20 0.25 logic, because the assumption about constant number
Cell-count reduction rate of infected cells (dY Idt = 0) analytically leads to
Fig. 5. Maximal frequency of infected cells during the hypothet- nonsense: that the number of uninfected cells X is also
ical HIV infection in a CD4+ pool of lymphocytes as a function constant (X = a I 13). Thus, the final conclusion made
of the final relative cell count (in ratio to its initial value in the in the work, that some values of the model parame-
very beginning of the infectious process). The relative value of the
cell immigration rate (regenerative power of the immune system) is ters could explain the observed values of viral burden
depicted near the corresponding curves. during the asymptomatic phase and CD4+ cell loss in
AIDS patients, is incorrect.
In summary, the intuitive qualitative statement that
example, to explain lO-fold cell loss (the curve cor- low viral burden cannot explain the observed effect
responding to the value f3la = 2.50 on Fig. 4), the of the significant decrease of the CD4+ cell counts
fraction of infected cells has to reach 0.4: this is 400- has been confirmed by quantitative analysis. Having
40-fold greater than the upper bound of the experi- been estimated quantitatively, this inconsistency is at
mentally observed value (0.001 ... 0.01), reported in least a 2S-S00-fold one. In other words, the simple
Pantaleo et al. (l993a, 1993b). HIV-mediated cytopathic mechanism of AIDS is not
The inconsistency between the putative cytopath- compatible with known facts about the low viral bur-
ic action of HIV and the known facts becomes even den during the asymptomatic phase and the significant
stronger if a more realistic assumption is made about CD4+ cell loss in AIDS patients.
the regenerative power of the immune system - that is
A > O. To make rsults of analysis more perceptible the

4.2 Is the high HIV burden reported real?
The interpretation of experimental results in the works
(Pantaleo et at., 1993a, 1993b; Embretson et at., 1993)
is based on the postulate about absolute, or at least
very high, specificity of nucleic acid hybridization.
The main experimental methods used were in situ DNA
and RNA hybridization and polymerase chain reaction
(PCR) followed by a hybridization-based procedure to
detect the products of the reaction. Positive hybridiza-
tion signals have been interpreted as an ultimate proof
of HIV-1 presence in the cells, and the magnitudes
of the signals were used for quantitative estimation of
the frequency of the HIV-infected cells. What follows
casts some doubt on the validity ofthe final conclusions
about high viral burden in lymphoid tissue.
From the logical point of view, it is almost impos-
sible to prove high specificity without a 'gold stan-
dard' - another method which is more reliable, but
based on some alternative principles. As far as I know,
DNA or RNA hybridization has no such rival tech-
nique. The use of a negative control cannot prove
specificity: it is easy to find a sample which does not
demonstrate hybridization with the probe, and a neg-
ative result cannot exclude false positive signals with
other samples. But any counter-example of false pos-
itive hybridization signals casts serious doubts on the
scientific credentials of the postulate about specificity
of the hybridization test.
There are at least two counter-examples which are
probably not widely known. The first is a work (Rogaev
& Shlensky, 1990) devoted to the use of a newly cloned
DNA probe red-I, which is a fragment of the env-gene
ofHIV-1, for DNA fingerprinting of human DNA. Suc-
cessful use of the red-l DNA probe for genotyposcopy
of liver DNA from rats was also reported (Prima et al.,
1993). In other words, a fragment of the HIV-1 genome
demonstrates strong hybridization signals with many
digestive fragments of the DNA from various tissues
of different species. It is clear that such a signal cannot
be interpreted as the presence of HIV-1.
Thus, fragments of the HIV-1 genome demonstrate
strong hybridization signals with a wide range of nucle-
ic acids which do not belong to HIV. Therefore, the
interpretation of such a signal as an ultimate proof of
HIV presence is not correct.
Moreover, even if the positive hybridization is real-
ly caused by HIV nucleic acids, this does not mean
that the virus is active and can really cause a cyto-
pathic effect. There are at least two plausible expla-
nations for the presence of the DNA fragments which
77
are usually thought to belong to HIV. The first one
is within the modern paradigm of virology: the frag-
ments belong to a provirus which is not an infectious
agent itself. The second one is more radical. It is the
endogenous (or cellular) hypothesis formulated by the
author. According to this hypothesjs, the nucleic acids
which are thought to belong to HN are the fragments
of the human genome that are normally 'silent' but can
take part in protein synthesis under certain conditions
in some groups of cells (for example, CD4+ lympho-
cytes) in vivo or in vitro. For more details see Section
6.4.
The only reliable way to prove the presence of a
virus and to estimate its amount quantitatively is to use
techniques which include direct isolation of the virus
and estimation of the number of its infectious particles
by direct count of cytopathic zones in an appropriate
immobilized cell culture (something like the classical
phage experiments in molecular genetics). Until such
methods have been used, any statement about the pres-
ence of an infectious agent and indirect quantitative
estimates of its amount are premature and speculative.
5. Explanation of some peCUlarities of AIDS epi-
demic
5.1 Why is the gay community highly susceptible to
AIDS?
According to the CDC, the homo- and bisexual men
form up to 70% of all the new AIDS cases every year,
while the men who are not indicated as belonging to
known risk groups form only 10% (Centers for Disease
Control, 1993a). Taking into account that gays form
only 5 to 10 percent in the US male population, we have
to conclude that annual AIDS risk for the mentioned
category is 140 to 70 times higher than for the general
population (if the share of homo- and bisexual men in
general US population is lower than the 5-10 percent,
the figures are higher).
Moreover, these figures (70-140 times) probably
reflect only the lower boundary of the real value of rel-
ative AIDS risk for gays in ratio to the general popula-
tion. This is because the 10% of representatives of the
general population among new AIDS cases appears to
be overestimated: it includes such exposure categories
as 'Heterosexual contacts' and 'Other/undetermined'.
To fit these categories it is enough to be not a homo-
or bisexual man, not an injecting drug user: other
known factors negatively affecting the general health
78
and immune status are not taken into account. Thus,
to consider these 10% of AIDS patients as representa-
tives of the general population is not correct. The true
ratio of AIDS risk for a gay to that of a representative
of the general population (free from other immunosup-
pressive factors, including those not being taken into
account by official statistics) seems to be much higher
than 70-140 times.
The official statement that peculiarities of gay sex-
ual contacts, mainly anal sex, can explain such a dif-
ference through the putative high probability of HIV
transmission during anal intercourse looks to be dubi-
ous. Anal sex, for example, is quite common in the
heterosexual population, but this has not caused an
increased incidence of AIDS among those who use this
sexual practice. Some other factors are responsible for
the AIDS risk in this category.
According to P. Duesberg, a factor causing high
rates of immuno-deficiency in the gay community is
the extensive use of sexual stimulators, especially by
those who have a high frequency of sexual contacts
(Duesberg, 1992a).
A third possible factor compromising the immune
system in gays is the massive use of wide-spectrum
antibiotics in order to prevent sexually transmissi-
ble diseases. These antibiotics eliminate the natural
microflora of the body. This, in turn, provides the
opportunity for other bacteria, 'foreign' to the immune
system, to proliferate and affect the immune system by
their antigens which are 'foreign' to it. Such a stim-
ulation of the immune system by a wide spectrum of
antigens can compromise the immunity.
Thus, the drug hypothesis provides a much more
persuasive explanation of the fact that homo- and
bisexual men are extremely (in relation to the gen-
eral population) susceptible to AIDS than the official
one does.
5.2 Why is the AIDS incidence extremely high within
specific groups of the population
The main pecularity of the AIDS epidemic is that the
disease incidence dominates in specific groups of the
population. According to the CDC, more than 90% of
all AIDS patients belong to one of the following risk
groups:
(a) homo- or bisexual men;
(b) injecting drug users;
(c) recipients of blood and blood components;
(d) born in Pattern-IT countries;
(e) sexual partners of injecting drug users
(Centers for Disease Control, 1993a).
It is obvious that all these groups are influenced
by known immuno-suppressive factors: the factors for
homo- and bisexuals are specified above; the bad health
state of injecting drug users is well known; recipi-
ents of blood and its components have compromised
health; emigrants from the Pattern-II countries are
mainly black and hispanic, with lower income, worse
medical service and nutrition; the health of recipients
of blood and its components is already compromised,
which itself causes the necessity of transfusion; sex-
ual partners of injecting drug users, in large part, use
recreational drugs.
Moreover, there is an up to 5 times higher rate of
AIDS incidence for blacks than for whites (Centers for
Disease Control, 1993c). This correlates with the fact
that the black population on average has lower income,
higher probability of malnutrition and drug use, and
worse medical service. All these factors compromise
general health status, including the state of the immune
system.
In summary, AIDS is widely spread in certain
groups of the population, which is influenced by
the factors that decrease the general health state and
immune status, directly or indirectly.
5.3 Why there is no exponential growth of AIDS in the
general population?
Although the observable saturation of the growth curve
of new AIDS cases within the AIDS risk groups is
explainable by the official theory, if AIDS were an
infectious disease, an exponential growth of AIDS cas-
es would be observed in the general population.
If AIDS is really a sexually transmissible disease,
taking into account that protected sex is not general-
ly practiced, exponential growth of AIDS incidence
would be observed in the general population. If even a
small percent (in reality this percent is rather high) of
the general population practiced unprotected forms of
sexual intercourse, exponential spread of the infection
would be an inevitable consequence.
5.4 Explanation of the temporal trends of the AIDS
epidemic
The official theory has also failed to provide a plau-
sible explanation for the temporal behavior of AIDS
incidence: the beginning of the epidemic in early 1980s
was followed by a rapid growth of annual rates of new
cases. Duesberg's explanation looks to be much more

Ratio N(t)/N(t-1)
3.5
3.0
2.5
2.0
1.5
1.0
1882 1883 18841885 1888 1887 1888 18881880 1881
t (year)
Fig. 6. Ratio of the annual AIDS incidence in the USA to its value
during the previous year; exponential growth would correspond to a
constant value of this ratio.
plausible: the end of 1970s and the beginning of the
1980s coincide with the outburst of a new 'epidemic'
of drug use in the USA, associated not only with quan-
titative changes in the drug use, but with appearance
of new drugs, mainly more dangerous synthetic drugs,
on the narcotic black market (Duesberg, 1992a).
Moreover, any epidemic of a really infectious dis-
ease, at least in its early phase, has to demonstrate
exponential growth. A specific feature of exponential
dynamics is the constant ratio of the number of new
cases during a year to the number having occurred
during the previous year. The values for the AIDS epi-
demic in the United States are shown in Fig. 6. The
decreasing tendency of this ratio is obvious even at
the earlier phases of the epidemic. Thus, exponential
growth of incidence for the AIDS epidemic has not
taken place.
It is probable that immuno-suppression is also
caused by some groups of new synthetic chemicals
which are used not only in recreational drugs and
aphrodisiacs, but in medicines, food production, and
so on. The question remains open what achievements
in the technology of chemical synthesis took place in
the 1970s, and what new synthetic chemicals came into
being that could cause immuno-suppression. Extensive
and detailed epidemiological studies with a good sta-
tistical design and elaboration could shed new I ight on
the problem.
79
6. Does a positive test for UIV really mean infec-
tion?
The validity of the traditional interpretation of a pos-
itive HIV-test as reliable evidence of HIV infection
is questionable (Papadopulos-Eleopulos, Turner &
Papadimitriou, 1993). What follows is an addition to
this criticism.
6.1 Possible causes of a positive test
The interpretation of positive results of HIV-tests is
under the influence of the general belief in the abso-
lute or at least very high specificity of immunochem-
ical reactions. Positive reaction of blood serum with
the HIV-proteins which are used in the test-system
is usually considered as evidence of the presence of
antibodies against HIV-proteins. There are several rea-
sonable objections against such an interpretation of
HIV-antibody tests.
It is necessary to take into account that a positive
result of a test means nothing more than that blood
serum contains proteins which have some affinity to
the proteins used in the test-system (the latter ones
presumably belong to HIV). There are at least five
logically acceptable explanations of a positive HIV-
test. They can be briefly summarized as follows:
(1) The positive reaction is caused by the presence
of antibodies against HIV, and the virus itself is
really present in the organism. This is the official
interpretation.
(2) The positive reaction is caused by antibodies to
HIV, but HIV is not currently present in the organ-
ism; the response of the immune system to HIV-
proteins is due to the contact with HIV in the past.
(3) The positive reaction to HIV-proteins is caused
by immunological cross-reactivity, when antibod-
ies produced against some foreign proteins demon-
strate affinity to HIV-proteins because of similarity
in some of their antigen determinants.
(4) The positive reaction is caused by non-specific
immunological reactivity, when blood serum, after
the immune system has been stimulated by a wide
spectrum of antigens, demonstrates affinity to a
wide range of proteins, including those which are
thought to belong to HIV (for details see Section
6.3).
(5) The proteins used in the test-systems really do not
belong to HIV, but they are proteins of pure cellu-
lar nature. They are not coded by some exogenous
nucleic acids but by some fragments of the human
80
genome that are normally 'silent', which can be
initiated under some specific conditions. Being
produced by lymphocytes after some changes in
their normal metabolism, such proteins initiate an
immunological response because they are foreign
from the viewpoint of the immune system (for
details see Section 6.4).
Thus, at least four mechanisms other than HIV
presence may cause a positive reaction in HIV-
antibody-test systems. It is not understandable why
we should accept the first out of the above five inter-
pretations and reject four others. Thus, it seems to be
useful to pay more attention to the last three items,
especially to the fifth one, called here 'the endogenous
hypothesis' or 'cellular hypothesis'.
6.2 Immunological cross-reactivity
Although immunological reactions are believed to be
highly specific in respect to the proteins which have
stimulated them, there are known phenomena which
could explain false positive reactions. One of these
phenomena is immunological cross-reactivity. In this
case, antibodies produced against a foreign protein
demonstrate affinity to other proteins, which differ con-
siderably from those having initiated the reaction, but
have some similar antigen determinants with the latter.
For example, it is a well known fact that vacci-
nation against hepatitis-B virus frequently results in a
positive HIV-test for some period. Another example
is TB patients: among them up to 70% demonstrate
positive results of tests for HIV (Frieden et al., 1993).
According to the official view, this is because these
patients have AIDS, and their TB is a consequence of
the compromised immune system. But the alternative
explanation is also plausible, that the positive HIV-
test is a result of cross-reactivity between antibodies
against TB-specific proteins and the proteins used in
HIV-test systems (Papadopulos-Eleopulos, Turner &
Papadimitriou, 1993).
There are other examples of seroconversion and
production of antibodies against the putative HIV pro-
teins (p 17, p31, p41, p55) caused by stimulation of
the immune system by antigens unrelated to HIV, for
example, by donated Rh+ serum (Burinsky et al., 1988)
as well as by other non-HIV antigens (Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993).
6.3 Non-specific immunological reactivity
Another immunological phenomenon which can cause
false-positive results in HIV-antibody tests is non-
specific reactivity. An example of such a non-specific
reaction of the immune system is 'immunological
shock' after intensive stimulation by a wide spectrum
of antigens.
A typical example is such a shock caused by trans-
fusion of blood or its components, especially if those
have been obtained from large numbers of donors (Sha-
balin & Serova, 1988). This shock results, for instance,
in poly-agglutination easily observed on test panels of
erythrocytes: a few days after the transfusion, blood
serum demonstrates agglutination for a wide spec-
trum of test erythrocytes with various surface antigens.
Thus, some abnormal states of the immune system,
especially that caused by its stimulation by multiple
antigens, lead to positi ve immunological reactions with
a wide range of proteins unrelated to those used for the
stimulation. The widely accepted postulate about high
specificity of the immuno-chemical reactions does not
work in these cases.
The phenomenon of non-specific immunological
reactivity looks to be a plausible explanation of the fact
that HIV-positives also demonstrate a high percent of
positive antibody tests for hepatitis virus, herpes sim-
plex virus, cytomegalovirus virus, and a wide spec-
trum of other antigens (Centers for Disease Control,
1990; Papadopulos-Eleopulos, Turner & Papadimitri-
ou, 1993). The phenomenon can also explain why
hemophiliacs and recipients of blood and its com-
ponents from multiple donors frequently demonstrate
HIV-antibody sero-positiveness. As for retroviruses,
'the scientific literature abounds with data which show
the widespread presence of nonspecific interactions
between retroviral antigens and unrelated antibod-
ies' (Papadopulos-Eleopulos, Turner & Papadimitriou,
1993).
The non-specific reactions of the immune system
caused by contact with a wide spectrum offoreign anti-
gens seem to be a plausible explanation of the high fre-
quency of HIV-antibody positiveness observed among
gay men and injecting drug users. This is because these
groups of the population are exposed to many foreign
substances: semen, drugs, and others (Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993).
Although the phenomenon of non-specific reactiv-
ity does not fit the modern paradigm of immunolo-
gy and appears to present a challenging problem for
scientific investigation, the nature and mechanisms

of the non-specific immunological reactions remain
unclear and lie beyond mainstream research in the field
of immunology and related areas. To reveal the true
causes of the positive reaction between blood serum
and HIV-test systems, and to estimate the role of the
immunological cross-reactivity and non-specific reac-
tivity, specific studies have to be conducted.
6.4 Hypothesis about possible endogenous (cellular)
origins o/the 'HIV-proteins'
HIV-test systems are based on the use of proteins which
are supposed to belong to the virus. Affinity of the
blood serum to these proteins is being traditionally
interpreted as evidence of the presence of antibodies
against HIV-proteins, and, hence, of HIV infection.
But why should we believe that these proteins really
belong to a virus which is an object exogenous to the
organism?
It is useful to take into account that these putative
HIV-proteins are extracted from living cell cultures of
human lymphocytes, and, thus, are produced by these
cells. According to the modern paradigm of molec-
ular biology, most of the human genome is 'silent'
- that is the proteins corresponding to the nucleic
acid sequences of this genetic material are not usually
being produced. At present, we know too little about
the mechanisms which are responsible for the control
of activity of various parts of the genome. For exam-
ple, it is not clear why different parts of the genome
are active in different groups of cells, and under dif-
ferent physiological conditions. It is quite probable
and logically acceptable that under certain conditions
some part of the normally silent genetic material may
become active and new proteins may be produced.
The central idea here is that the facts observed in
the experiments, which traditionally are being inter-
preted as ultimate evidence of cell-to-cell viral infec-
tion, have another plausible explanation. It is usual-
ly assumed that any infectious process within a cell
culture is obviously associated with transmission of
exogenous (in respect to the organism the cell line orig-
inates from) self-replicating genetic material (a virus).
This material becomes active in susceptible cells and
causes the production of corresponding proteins (in
viral particles) which are not usually produced by this
cell line.
But another explanation is also plausible: cell-to-
cell 'infection' is caused by transmission of some fac-
tors of cell metabolism that do not carry any genetic
information. The factors only stimulate a chain of bio-
81
chemical processes which lead to the switching on of
a normally 'silent' part of the genome. If these initial-
izing factors or some catalyzers for their synthesis are
produced in this chain of in-cell biochemical transfor-
mations as a byproduct, the feedback is closed and we
might observe a pseudo-infectious process. Almost all
the observable signs of such a pseudo-infectious pro-
cess in vitro as well as in vivo are indistinguishable
from a true infectious process (that is accompanied by
transmission of foreign genetic material).
As for observable serological consequences, if the
activity of some part of the genetic material in some
groups of cells has switched on in an organism with
an already developed immune system, the correspond-
ing proteins very likely will cause an immune response,
including antibody production. This is because the pro-
teins are new or 'foreign' from the viewpoint of the
immune system that has not met them before. Thus,
observable signs of a cell-to-cell infectious process in
vitro and seroconversion itself are well compatible with
both the classical and proposed explanations.
The cellular hypothesis can also explain why trans-
fusion of blood or its components from an HIV-
antibody positive donor can cause seroconversion in an
HIV-negative recipient. It is quite probable that such
a seroconversion is due to transition of the putative
'HIV-proteins' that stimulate the recipient's immune
system, and induce antibody production against the
proteins. Because the proteins are used in test systems,
the serum of the recipient can react with them, and the
recipient becomes 'HIV-positive'.
The idea of a crucial experiment which could shed
some light on the problem and distinguish between the
two rival explanations has been proposed by the author
and described in Section 8.5.
7. The general acceptance of the HIV/AIDS theory
creates serions bias in AIDS official statistics
A main aim of collecting statistics is to provide an
objective and unprejudiced picture of complex phe-
nomena, and finally to help us to improve our knowl-
edge about them. A central principle is that our a priori
hypotheses about these phenomena must not influence
the data gathering and interpretation procedures. If this
principle is violated, the statistics available can lead us
to erroneous conclusions. Was the above mentioned
requirement being met during the collecting of the
official AIDS statistics? The answer is negative: the
82
general belief in the HIVI AIDS theory has caused seri-
0us bias in statistics in favor of the official theory.
7.1 Vicious circles of AIDS definition
Although the CDC's AIDS definition does not neces-
sarily imply a positive HIV test, for most physicians
a positive test for HIV is a synonym of HIV-infection,
and AIDS diagnosis implies HIV-infection. Because
all AIDS cases are registered within the category 'HIV
infection' , although a relatively large percentage of the
AIDS cases have not been supported by positive tests
for HIV, an illusion has been created that all AIDS
patients are HIV-positive.
Official CDC statistics do not provide information
about what percentage of AIDS diagnoses were sup-
ported by a documented HIV-test. According to the
CDC's director of the HIV/AIDS division, a positive
test for HIV had not been documented for 43,606 out
of the 253,448 AIDS cases registered in the United
States by the end of 1992 (Duesberg, 1993).
On the other hand, a positive result of an HIV-test
significantly increases the probability of the patient
being classified as having AIDS. In other words, not
all the AIDS patients reported by the CDC are really
positive for HIV, and a number of true AIDS cases are
not diagnosed correctly because of the negative test.
The latter is supported by a simple analysis of the US
mortality trends (for details see Section 3).
Thus, the official statistics itself, being based on
the belief in HIVI AIDS theory, leads to the incorrect
conclusion that the correlation between AIDS and HIV
is absolute.
7.2 'Proofs' of a sexual mode of HIV transmission
7.2.1 homosexual contacts
According to the official theory, the main mode of
HIV transmission is homosexual contacts. How is this
transmission being detected? If an HIV-positive homo-
or bisexual man has reported a sexual contact with
another HIV-poJitive man, the conclusion about sexual
HIV transmision is being made. Is such a conclusion
correct?
The main principle of statistical inference is to esti-
mate the P-value for the null hypothesis - that is, the
probability that the observed effect may be explained
by pure chance. The null-hypothesis cannot be rejected
until the P-value is small enough (normally less than
0.01 or 0.05). Within the present context, the null-
Probability
1.0
0.8
0.6
0.4 I+--/-~------------"i
0.2
0.0 L-.,--,--'--'--..L-...L-..L--'---'---'--'--'--'--'-~
1 6 10 16
Number of partners
Fig. 7. Probability of finding at least one HIV-positive among
N sexual partners of a homosexual man. The frequency of
HIV-positives in the most sexually active part of the homosexu-
al population is depicted above the corresponding curves (lower
bound, the mean value. upper bound; USA. STD clinics).
hypothesis is that HIV is not a transmissible agent,
and that the presence of HIV-positives among the sex-
ual partners of an HIV-positive, whose case is under
investigation, may be explained by chance and random
coincidence. As for real causes of the high prevalence
of HIV-antibody positives in the gay sub-population
with high promiscuity, it may be explained by non-
infectious factors unrelated to HIV and associated with
lifestyle.
The P-value of interest is the probability of find-
ing at least one HIV-positive among N hypothetical
partners drawn at random from the same group. The
null-hypothesis (that HIV is not transmissible through
homosexual contacts) may be rejected only if the P-
value is relatively small, traditionally less than 0.01 (or
at least, 0.05). As a representative sample of the most
sexually active and promiscuous part of the gay com-
munity, the patients of sexually transmissible disease
clinics have been used for the following calculation.
Among them, the percentage of HIV-positives varies
in different states and metropolitan areas from 17 to
60; the mean value is 32 (Centers for Disease Control,
1991).
The rate of probability that among N partners at
least one is positive for HIV because of pure chance
has been calculated for three frequency rates of HIV-
positives among the sexual partners: 17% (the lower
bound), 32% (the mean value), and 60% (the upper
bound). The results obtained for the various numbers
of sexual partners in the scope are presented in Fig. 7.

It is easy to note that, even among a small number of
hypothetical partners taken at random, the probability
of finding at least one who is positive for HIV is much
higher than the threshold value 0.01 (0.05). Taking
into account that a great part of the sexually active
segment of homosexual population have had tens and
hundreds of partners during the last several years, the
null-hypothesis is well compatible with known facts
and cannot be rejected on the basis of the information
available.
Thus, there are no factual reasons to make any con-
clusions about homosexuals transmission ofHIV. Fur-
thermore, to draw such a conclusion from the presence
of HIV-positives among mUltiple partners of an HIV-
positive homosexual man is to make a rather egregious
methodological error and to violate well established
and generally accepted principles of statistical scien-
tific inference.
7.2.2 Heterosexual contacts
According to the CDC, among AIDS patients 3-4%
of males and up to 40% of females have acquired
AIDS through HIV transmission during heterosexu-
al contacts (Centers for Disease Control, 1993a). For
an AIDS patient, to be classified by official statistics
as having acquired AIDS through sexual contacts, it
is enough to report at least one contact with a sexual
partner out of the following categories:
(a) injecting drug user;
(b) bisexual men (for women only);
(c) person with hemophilia;
(d) person born in a Pattern-II country;
(e) transfusion recipient with HIV infection;
(f) HIV-infected person, risk not specified;
or,
(g) to be born in a Pattern-II country;
(Centers for Disease Control, 1993a).
It is obvious, that only two, (e) and (f), ofthe above
categories imply direct evidence of HIV-antibody pos-
itiveness of a partner. The (g)-category does not even
imply a sexual contact with a representative of an AIDS
risk group. Even if the percentage of HIV-positives
among the partners in (a) and (b) categories is estimat-
ed from the data for patients of SID clinics (Centers for
Disease Control, 1991), the probability of the partner
to be really positive for HIVis 32% for (a), and 2.5-5%
for the (b) category. It is obvious that the above figures
reflect only the upper boundary of the real percentage
because patients of the SID clinics demonstrate much
higher rates of HIV-antibody positiveness than oth-
83
er representatives of the same categories, (a) and (b).
Therefore, most of the AIDS patients with a positive
HIV-antibody test have been reported by the CDC as
having acquired AIDS through heterosexual contacts
without any factual reasons.
Furthermore, most of the patients are highly
promiscuous, and the number of sexual contacts with
one partner is usually small. It is enough to report even
one contact with an HIV-antibody positive partner to be
classified as having acquired AIDS through heterosex-
ual transmission. On the other hand, the lower bound
of the number of heterosexual contacts that might lead
to seroconversion is estimated as 1000 (Dues berg,
1992a). Therefore, if an AIDS patient has reported
a contact with an HIV-antibody positive partner and
has been classified (in accordance with the CDC's cri-
teria) as having acquired AIDS through heterosexual
transmission, the probability that he or she has really
acquired HIV through heterosexual intercourse is only
1: 1000.
It is necessary to note that the above mentioned
estimates of the probability of HIV-transmission do not
mean that HIV is really an infectious agent transmis-
sible through heterosexual contacts: the figures only
mean that if the probability of transmission during one
intercourse were higher than 1: 1000, the frequency
of seroconversion among the HIV-negative partners of
HIV-antibody positives would be higher than what has
been really observed.
In summary, to draw the conclusion about hetero-
sexual HIV transmission based on the CDC's crite-
ria described above is very subjective and prejudiced.
Only the general faith in the viral theory can explain
why such egregious errors have been made during the
development ofthe CDC's criteria of heterosexual HIV
transmission. These criteria are not acceptable: they do
not meet conventional standards of scientific inductive
inference, and have to be reappraised.
7.3 Elimination ofrelevant causal factors from analysis
A main negative effect caused by the general accep-
tance of the official HIV/AIDS theory is that only a few
factors, consistent with the official theory, are being
taken into account and included in questionnaires. For
example, such immuno-suppressive factors as the use
of various drugs, peculiarities of lifestyle, inclination
to psychological stresses, general health state, diseases
in the past, and many others (which may be relevant to
the problem of the real causes of AIDS) are eliminated
from the analysis.
84
In fact, the official statistics, although millions of
dollars have been spent, are biased and cannot be fruit-
fully used to reveal real causes of AIDS. A much more
versatile and reliable picture of the AIDS epidemic
could be achieved if the CDC's data-gathering pro-
cedures were not so biased by the acceptance of the
official or any other theory.
8. The questions to be answered, and some areas of
future research
The above performed analysis of the official
HIV/AIDS theory has revealed that scientific creden-
tials of the theory are questionable, and basic prin-
ciples for interpretation of the results of experiments
and observations, generally accepted in the scientific
community, have been violated. What are the main
questions to be answered, and what studies have to be
performed to clarify these questions? Some of them
may be briefly specified as follows.
8.1 Improving the procedures for collecting of statisti-
cal information
Any scientific investigation of such a complex problem
as AIDS has to be based on an unprejudiced analysis
of all possible factors which could affect AIDS inci-
dence and mortality. Of course, the problem has no
easy solution because any human being is influenced
by lots of factors during life, and it is a rather difficult
thing to gather relevant information having avoided
any bias. Unfortunately, the official medical statistics,
being influenced by the official theory, use data gather-
ing procedures which are seriously biased in favor of
the viral theory (for details see Section 7).
Thus, if we wish to have an objective and reli-
able picture of AIDS, the first step to be made is to
establish a relevant mechanism for the collection of
statistics. This implies that for every AIDS patient or
an HIV-positive, all the factors which could influence
the general health state and that of the immune sys-
tem have to be registered (irrespective of their corre-
spondence to any theory). Some of these factors are:
annual income; quality of nutrition; quality of medical
care; health status during the life, including various
diseases in the past; vaccinations; use of various kinds
of drugs, separately for different categories: antivi-
ral drugs (AZT and others), antibiotics, recreational
drugs, sexual stimulators, and so on; general character
of lifestyle: physical culture, sports, physical activity,
stresses, and others. The list of factors for registration,
of course, is not complete, and other factors still have
to be added.
8.2 Analysis of lifestyle associated factors
The population of HIV-positives and AIDS patients
is highly inhomogeneous in respect to the course of
disease, even if they belong to one of the known
AIDS risk groups. For example, according to J. Wells
(Wells, 1993), among the 1.5 thousand members of
the Continuum group, only four deaths have been
registered during a 15-month interval. Two of these
deaths have not been associated with AIDS; the oth-
er two have occurred in AIDS patients under AZT
treatment, and might be explained by the well known
toxicity of the drug. The Continuum group includes the
HIV-positives and AIDS patients who have made their
lifestyle healthy and avoid drug use, including antiviral
therapy. Thus, mortality among AIDS patients depends
drastically on their lifestyle. These facts are usual-
ly ignored by the proponents of the official HIVI AIDS
theory; the 'explanation' that long survivors have some
genetic predisposition is accepted by them as persua-
sive.
The significant difference in mortality among HIV-
positives and AIDS patients with different lifestyles
deserves to be analyzed thoroughly. Thus, it will be
important to conduct detailed study of the difference
in the lifestyle associated factors between the long-
survivors with HIV and AIDS, and those who have a
short period between the first positive HIV-test and
AIDS diagnosis, and between AIDS diagnosis and
death. It is important to focus on all the possible fac-
tors deteriorating the immune system, not only on those
implied by the official theory.
8.3 What is the positive HIV-test really caused by?
The general belief in the postulate that a positive HIV-
antibody test is a reliable proof of infection has no
strong factual support. This is a mental stereotype,
rather than a scientific fact. The main shortcoming of
the mainstream research is the violation of the basic
principles of objective study: blind protocol of exper-
iment, relevant randomization of samples, and use
of matched control. Several factors other than HIV-
infection that can cause a positive test are specified in
Section 6.
The only actually reliable method to estimate true
specificity and sensitivity of the HIV-tests is to per-

form extensive studies using direct HIV-isolation as a
'gold standard' of infection. The main features of such
a study have to be a fully blind protocol of exper-
iment, analysis of mutual correspondence between
results reported by different laboratories, blind ran-
domization of samples, and the use of really matched
controls - that is, patients with the same symptoms,
and the same lifestyle. The use of really matched con-
trols is of particular importance. This requirement has
not been met in the studies of this kind. The direct
experimental study of HIV-test specificity with the use
of direct methods for HIV isolation would be useful
irrespective of which theory is true.
HIV-antibody positiveness can be caused by several
factors differing from HIV (section 6.4; Papadopulos-
Eleopulos, Turner & Papadimitriou, 1993). HIV-
antibody tests, having been performed several times
during some interval, are frequently not reproducible.
This is why it will be important to make it a normal
practice of sero-monitoring to perform tests periodical-
ly for those patients who have demonstrated a positive
test for HIV.
8.4 What is the meaning o/the low CD4+ cell counts?
With the advent of reliable and accessible methods for
estimation of the lymphocyte phenotype, the decrease
in the CD4+ T-cell count has become a main laboratory
criterion of full blown AIDS. But does the decrease
of the cell count really mean a disease? Do all such
patients really have serious problems with their health?
Of course, the patients with seriously compromised
health may demonstrate a decrease in T-cell count, but
is the decrease always associated with severe health
problems?
According to J. Selvey, for instance, there are a
number of cases when individuals with zero or very
low (3 to 15) T4-cell counts are not suffering from any
opportunistic infection. Moreover, there are perfectly
healthy HIV-negative individuals with their CD4+ cell
counts substantially lower than what the CDC says is
normal (Selvey, 1993).
Thus it is important to perform extensive studies
in various categories of the population in order to find
and investigate those who have low CD4+ cell counts
but are negative for HIV. Moreover, it is extreme-
ly useful to analyze temporal behavior of CD4+ cell
counts, because they have a strong tendency to sig-
nificant temporal variation within a wide range. The
question remains as to what factors cause such a tem-
poral variation of counts within the same individual.
85
8.5 Does HIV really exist as an exogenous transmissi-
ble agent?
In Section 6, the hypothesis has been formulated that
HIV does not really exist as an exogenous transmissible
agent, and the putative HIV-proteins in blood and tis-
sues are of pure endogenous (cellular) nature: they are
produced because some parts of the genome, normally
'silent', become active; the putative HIV proteins are
produced by cells using this previously silent genet-
ic information which belongs to the normal human
genome. According to this hypothesis, there is not any
transmission of genetic material from cell to cell; it is
only some factors that change normal cell metabolism
and switch some normally 'silent' genetical materi-
al on, but do not carry any genetic information, that
cause the observable signs of cell infection in vitro.
The question to be answered is: Is there any trans-
mission of exogenous genetic material (nucleic acids)
in the experiments with putative HIV isolation, or are
the proteins, presumably belonging to HIV, produced
by 'infected' cells using endogenous (cellular) genetic
information?
The crucial experiments, which could support or
reject the above hypothesis, may be performed accord-
ing to the following experimental design. A main
property of the putative virus which makes such an
experiment possible is the high degree of genetic vari-
ation: nucleic acid 'fingerprints' of isolates from dif-
ferent individuals vary significantly. The central ques-
tion to be answered is: Does the difference in nucleic
sequences estimated after the putative virus isolation
reflect the difference in the virus genome isolated from
different individuals, or is this difference caused by
differences in the genome of cell cultures used for iso-
lation, or simply by bad reproducibility of the isolation
technique.
The initial material for the experiment is N samples
of blood or tissues from individuals with an easily
reproducible positive HIV-antibody test as well as from
healthy ones as controls, and M susceptible cell lines
obtained from different sources. Then, after all the
experimental materials have been randomized in blind,
N x M experiments for virus isolation have to be
performed (for each patient-cell-line pair) according
to a fully blind protocol. The next stage is to obtain
nucleic-acid fingerprints for each of the N x M infected
cultures according to one of the known techniques.
If we are really dealing with an exogenous trans-
missible agent, simple statistical analysis has to reveal
clear clusters: nucleic sequences obtained for samples
86
associated with the same individual have to demon-
strate strong similarity for all lines of susceptible cells,
while the fingerprints for different individuals have to
have a clear distinction irrespective of the cell lines
used for virus isolation. If the cellular (endogenous)
hypothesis formulated in Section 6.4 is true, clusters
will be observed for different cell lines, not individuals
(if the cell lines are genetically different enough), or
there will be no clear clusters at all (if the variation is
actually caused by low reproducibility of the isolation
techniques).
It is quite probable that the high genetic variability
of HIV reported earlier reflects nothing more than bad
reproducibility of the virus isolation techniques used.
Therefore, to make the experiment more reliable and
to check this hypothesis, several samples for each indi-
vidual have to be used, mixed and randomized in blind
with the samples from all other individuals. Of course,
this makes the experiment more expensive, but makes
it possible to estimate reproducibility of the virus iso-
lation method and increase the reliability ofthe results.
At least two requirements have to be met: (i) a ful-
ly blind randomization of all the experimental material
(the samples of infected cells and susceptible cell lines)
and blind protocol for all stages of the experiment
(to avoid any subjectivity); (ii) several passes of the
cell cultures after they have been presumably infected
before the fingerprinting procedure. The latter is nec-
essary to avoid any direct transmission of the intact
genetic material from initial samples. Otherwise, even
if the clusters exist for initial samples, they may simply
reflect the individual features of normal nucleic acids
of different individuals. This is because the traditional
co-cultivation techniques use mixed culture where one
cannot separate the presumably infected cells obtained
from individuals from those belonging to the suscep-
tible but non-infected cell culture. If HIV is really a
transmissible agent, the fitting of the above mentioned
requirements cannot deteriorate the clusters associated
with individuals.
9. Conclusious
(1) Even a 100% correlation between HlV-antibody
positiveness and AIDS (all AIDS patients are positive
for HIV-antibodies, and there are no AIDS patients
without HIV) cannot be used as proof of the causal role
of HlV in AIDS. This correlation is also compatible
to the same extent with alternative hypotheses, for
example, that an already compromised immune system
causes susceptibility to HIV infection (see Section 2),
or that some states of the immune system caused by
factors unrelated to HIV cause a false-positive test for
HIV-antibodies (see Section 6).
(2) There are several mechanisms in the data col-
lecting procedures, including those used for official
statistics, which tend to overestimate seriously the
HIV-AIDS correlation. The main cause of this overes-
timation is the general belief in the official HIV/AIDS
theory (see Sections 2, 7).
(3) There are clear trends in the US mortality statis-
tics which demonstrate that up to a thousand out of the
annual deaths from infectious diseases (not diagnosed
as AIDS) in reality are caused by the same factors as
the cases diagnosed as AIDS; these deaths are proba-
bly misclassified as non-AIDS because of a negative
test for HIV (see Section 3) ..
(4) The putative HIV-mediated cytopathic mecha-
nism of AIDS is not compatible with the known fac-
tors about viral burden in asymptomatic HIV-positives.
Direct quantitative analysis of the putative infectious
process in the CD4+ pool of cells demonstrates that
there is at least a 25-500-fold incompatibility between
the cell loss in AIDS patients and the maximal frequen-
cy of infected cells observed during the asymptomatic
phase (see Section 4).
(5) The non-infectious theory of AIDS provides
much more persuasive explanations of the main pecu-
liarities of the AIDS epidemic than the official theory
does (see Section 5).
(6) The official AIDS statistics in the US are seri-
ously biased in favor of the virus theory, because the
data-gathering and interpretation procedures are based
on the basic tenets of this theory. Moreover, the offi-
cial statistics fail to provide an objective picture of
the causal role of different potential factors of AIDS,
because these factors are not in its scope (see Section
7).
(7) The general belief that a positive test for HIV-
antibodies really means HIV infection, and that low
CD4+ counts are inextricably linked with disease, has
no serious factual background (see Section 6).
(8) The statements about homo- and heterosexual
modes of HIV transmission have no serious factual
support; the procedures used by the CDC to prove
such a transmision are not correct from the viewpoint
of normal standards of statistical inference.
(9) Despite the belief of adherents of the official
theory (as well as those of the alternative) that HIV
really exists as a self-replicating transmissible agent,
this statement is questionable and cannot be considered

as an ultimately proved fact. A hypothesis has been
advanced by the author that the putative HIV proteins
are of pure cellular (endogenous) nature; they are pro-
duced by cells under certain physiological conditions
because of the switching on of some normally 'silent'
parts of the genome (Section 6.4). Experimental study,
the idea of which is briefly described in Section 8,
could shed some light on the problem.
(10) Interpretation of large numbers of experiments
in the field of AIDS and HIV research is based on the
widely accepted belief that such physico-chemical pro-
cesses as immuno-chemical reactions and nucleic acid
hybridization are of absolute or at least very high speci-
ficity. There are lots of facts that cast serious doubt on
the validity of this postulate and demonstrate that the
probability of false-positive results is seriously under-
estimated (see Section 4.2, Section 6). The problem is
much wider than HIV/AIDS research and deserves to
be analyzed carefully.
Acknowledgements
The author wishes to thank Dr. Ingeborg Heinrich for
the fruitful critical discussion of some parts of the paper
which allowed them to be improved significantly; and
the Centers for Disease Control and Prevention for
HIV/AIDS statistics.
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Some mathematical considerations on HIV and AIDS

Mark Craddock
School of Mathematics, University of New South Wales, Sydney, Australia

Abstract

It is coinmonly accepted that HIV is both necessary and sufficient to cause the immunodeficiency and multiple
diseases seen in patients diagnosed with AIDS. In other words it is accepted that HIV is the cause of AIDS. Upon
this basis public health decisions in all Western countries regarding AIDS are made. However, many scientists now
question the role of the virus (Root-Bernstein, 1993). Questions that have arisen about the virus include whether or
not it is present in sufficient quantities to cause disease and whether or not AIDS is infectious. The former question
has been applied to by new studies using the Polymerase Chain Reaction (PCR) technique that claim to detect very
large quantities of virus in HIV+ patients at all stages of disease progression. I will examine these studies and show
that they do not truly answer the criticisms that have been levelled. They in fact give rise to more questions than
they answer. Predictions that one can make from them contradict the observed pattern of the disease. I will also
argue that data based upon the so called Quantitative Competitive PCR need to be treated with caution.

Section 1 viral load
Studies of viral load in HIV + patients have shown
that most patients rarely have more than 1 in 10 000
to 1 in 1000 T cells in the bloodstream infected with
HlV (Pantaleo et al., 1993). Recently Embretson et
al. claimed that there is 'massive covert' infection
of T cells in lymph tissue with HIV (Embretson et
al., 1993). It is now widely accepted among HIV
researchers that many more cells in lymph tissue are
infected with HIV than in the blood stream. A priori
this is extremely unlikely. Embretson et al. say that
1/4 of all T cells in the lymph nodes of HIV+ indi-
viduals are infected with HIV. Since T cells from the
lymph nodes migrate through the body and into the
blood stream in an essentially random fashion, then
the viral load in blood and lymph nodes, as far as T
cell infection is concerned, should be identical. The
only way that this would not happen is if somehow
HlV can alter the lymph node structure so that infected
T cells are trapped, unable to move to other parts of the
body. No plausible mechanism for this has ever been
suggested. But there is another objection to Embret-
son et al.'s claims. If HIV is present and replicating
in the quantities they claim, then how long would dis-
ease progression take? A simple mathematical model
can be used to predict what should happen. It seems to
imply that disease progression should be much faster
than what is actually observed.
A mathematical model for HIV T cell infection
Let us denote the total number of T cells present in an
HIV + individual n days after infection by
T(n)
And the total number of infected cells by
T;(n)
We are told that at any time the number of infected
cells is ~ of the total. Hence
T(n) = 4T;(n)
Further we are told that 1% of the infected cells are
actively producing HIV, and that these cells die. If we
assume that the total T cell count in the absence of HIV
is in equilibrium, then we must have
T(n + 1) = T(n)
This is taken from the observation that
T(n + 1) = T(n) - L+C
90
where L represents the number of T cells lost on a
given day, and C the number created to replace those
lost. This equilibrium implies that L = C, and so we
have the original equation.
In reality we might expect some oscillation, but this
model should be sufficient. The logic being used here
is straightforward. It is claimed that HIV is actively
killing T cells. Thus the deaths of T cells due to the
action of HIV represents a perturbation of the equilib-
rium position. We have to determine what this pertur-
bation is.
If we then include the infected cells that are express-
ing HIV, using the claim that these cells die we are led
to
T(n + 1) = T(n) - 1~T;(n)
Thus the T cell count after n days should be the
previous day's T cell count minus those T cells infect-
ed with HIV which have died. Note that the above
equation, by our previous argument, contains both the
T cells lost naturally and the usual replacement of the
lost cells. If we are to have a net depletion of cells, then
the above equation must hold (or perhaps a modified
version of it: see below).
Using the claim that at anyone time ~ of the total
cells are infected, we are led to
T(n + 1) = T(n) - 4~T(n)
Or
T(n + 1) = ~~~T(n)
This is a simple difference equation, the solution of
which is
T(n) =(~)nT(O)
Here T(O) is the original number of cells infected.
Of course this result assumes that T(O) =4T;(0).
So we have a concrete realisation of the decline in
the T cell count of an in HIV+ individual based on
a simple model constructed from Embretson et al.'s
data. What does this predict in practice? Well, if we
set n = 730 (i.e. 2 years after infection), then we find
that
T(730) = 0.16T(0)
In other words, this model predicts that the number
of T cells in a HIV + patient should have fallen by
84% in only 2 years. This is sufficient for an AIDS
diagnosis in the United States, although not elsewhere
if no opportunistic diseases have developed. We thus
have the question: why does AIDS take so long to
develop if HIV is the cause and if it is present in the
quantities that Embretson et al. say it is?
Clearly the model taken here is a very simplistic
one. There are a number of objections that can be made
to it. In response to these we can consider possible
modifications.
We may extend the time it takes the infected T cells
to die, by some arbitrary amount. Then our equation
for the total number of T cells would be
T(n + 1) = T(n) - 16oTi(n - k)
That is, the total number of T cells present is equal
to the number present the previous day, minus 1% of
the number of infected cells k + 1 days ago. This mod-
ification to the model does not change the qualitative
picture significantly unless one makes k very large.
The reason for this is that the behaviour of T( n) is
determined by the roots of the polynomial
..\HI _ ..\k - 4~ =0
This has one large root and k small roots. So for
example if k = 1, then the roots are approximately
.9975 and .0025. The behaviour of T(n) is then for
large n approximated by
(.9975tT(0)
Here we have assumed that T(O) is approximately
equal to T( 1). This behaviour is essentially the same as
=
for the original model. If we take k 2 then we have a
root near .9975, and two near .05 and -.05. Again the
behaviour is essentially the same as the original model.
For all reasonable values of k, the situation should be
described by the original model. By reasonable I mean
values of k small compared to the time frame in which
the disease is said to occur. And indeed, if HIV really
is causing T cells to die by its replication process, one
would expect this to occur on the same time scale that
replication proces takes, i.e. a few days. Thus the first
modification one can make to the analysis does not
qualitatively change matters. The disease should still
rapidly destroy the T cells in the lymph glands.
Of course one can make disease progression very
slow by choosing k large enough, but this produces a
logical problem. The purpose of the work of Embret-
son et al., at least in part, was to answer a criticism
of the HIV/AIDS hypothesis that HIV is not present
in sufficient quantities in HIV+ individuals to cause
disease. The objection was that if only 1 in 1000 T
cells were infected with HIV, then the virus would take
essentially forever to cause the disease. If one pushes
the killing time back too far, then this problem returns

in another form. We do not want the time HIV takes
to kill an infected cell in vivo to be essentially as long
as the life time of an uninfected cell. The entire basis
of our model is that the T cells being killed by HIV
are in addition to the ones dying naturally, and so they
are not replaced by the natural mechanisms for T cell
replenishment. If HIV takes too long to kill a T cell
then those T cells will be replaced as a matter of course
because the body was in a sense expecting them to die
around that time anyway, and so the replacement cell
will be already waiting. The conclusion from this is
that k should not be made too large.
Another alternative that presents itself is to assume
that the body, in response to the infection, starts pro-
ducing more T cells. This would lead to an equation of
the form
T(n + 1) = ~~~T(n) + r(n)
r( n) is a response function. It represents the num-
ber of additional cells the body is producing in response
to the destruction of T cells caused by HIY. A natural
question is: what form could r( n) take? We certainly
cannot make r( n) too large initially because the body's
response to the infection cannot be as large as the ini-
tial T cell count. Obviously it is untenable to argue that
the body suddenly doubles the number of T cells in
response to the action of HIY. The body can replace
about 5% of its T cells every 2 days (Duesberg, 1989).
So we would not expect the size of r( n) to be much
bigger than .05T(0). With this point in mind, let us
consider a few possibilities.
If we take
r(n) = 0
where C is a constant (the body produces a limited
constant response to the infection), then we have
T(n + 1) = ~~T(n) +0
The solution is:
The equilibrium state for the T cell count is thus 400C,
whereas the equilibrium state for Ti (n) is 100e. (Let-
ting n -+ 00 we see T( n) -+ 4000).
The consequence of this is that if the body has a
constant response to infection, then the virus will reach
an equilibrium state, and the T cell count will fall no
further. The precise equilibrium state depends upon the
value of C. If C is too high, then AIDS will not devel-
op. If it is too low, then the equilibrium state will be
91
less than 14% of T(O), and under the 1993 case defi-
nition the individual will have AIDS. This equilibrium
state will still develop quickly. So a constant response
to the infection will either see the infected individual
develop AIDS quickly (C too small) or the patient will
never have aT cell level < 14%T(0) (although oppor-
tunistics diseases may develop; this aspect is essential-
ly unpredictable). The point to be understood is that
with a constant response, the disease still progresses
rapidly.
Thus the response function r( n) cannot be a con-
stant. It must decline over time. It is also clear that if
r( n) has polynomial decrease, then this response will
not delay the onset of AIDS. For example if we take
r(n)=~
(1 + n)
we can solve the difference equation by iteration. We
obtain:
T(n) = G~tT(O) + reO) tk=l
),nk-k
Here ), = ~. If we take n = 730 in the above
series, and let reO) = .05T(0), we see that after 2
years, the T cell count will still be about 24% of its
initial value. After 4 years we find that the number of
T cells should have fallen to about 5% of its original
value. This clearly is not sufficient to add much to the
time taken for AIDS to develop. a linear decrease in
the response function only yields a logarithmic benefit
in the time it adds to disease progression. Obviously, if
we have an even faster decay in the response function
then it will add even less to the time for the disease to
progress.
Another possibility we can try is a logarithmic
decrease in the number ofT cells the body produces to
fight the infection. We would have something like
r(n) _ reO)
- (1 + logn)
So our equation for T( n) is
reO)
(
Tn+l )
= ( 399) ( )
400 Tn +(
1 + I ogn )
This does not describe what happens in HIV+ peo-
ple. For even small values of reO) this causes the T cell
count to rise quite substantially. It can quickly double.
(T(lOO) RJ 2T(0)forr(0) = .05T(0)).Arapidrisein
92
the number of T cells in the body is not what we want
our model to predict.
Another possible form for r(n) is r(O)a n . a is
some constant less than 1. Since we expect r(O) to be
smaller than T(O), then if a < !~~, little delay in the
fall of the T cell count will eventuate. The equation
is
=
T(n + 1) !~T(n) + r(O)a n
The solution is
,\ =!~. Noting that r(O) is no larger than .05T(0),
then substituting n =730 we see that the magnitude
of the decline is essentially the same. If a = .95 and
r(O) = .05T(0), then we find that T(730) is still
approximately 0.16T(0). Taking a smaller produces
even less benefit.
If a =
!~~, then the solution is
Again ,\ = ~~~. This response function actually
seems to give the right time frame for the onset of
AIDS. If we take n = =
2190, i.e. 6 years, and let r(O)
.05T(0), then we find T(2190) to be approximately
.46T(0), which is in the correct region for the T cell
count. After 10 years it predicts that the T cell count
should have fallen to about 2% of the original value..
There is, however, a problem with this that leads
me to reject this as a possibility. The T cell count is
supposed to be steadily falling in HIV+ individuals.
But if we take n =100 for this model of the T cell
count, we find T(100) is approximately 79 times the
initial count! Clearly this is untenable. It forces us to
conclude that r(O) must be very small. If we want
the T cell count to be of the same magnitude as T(O)
after 100 days then r(O) must be less than .002T(0).
This, however, kills the delay in the onset of AIDS.
IF we take r(O) = .002T(0), and use our expression
for T( n) we find that after 2 years the T cell count
is about .39T(0). After 3 years we have only 20%
of the original number of T cells remaining. In other
words we get nowhere near the claimed period of 10-
12 years (and rising) that HIV supposedly takes to
cause AIDS.
Clearly there are many possible response functions
that can be postulated which might extend the time
for AIDS development to the observed latency period,
while at the same time matching the small fall in the
number of T cells early in infection (Le. a model that
does not predict a drastic increase in T( n) early on).
But there remain many problems with the observation
of Embretson et al. Even if the body does start mass
producing T cells in response to the infection, there
is a very important point that has been overlooked so
far. It is untenable that the proportion of infected cells
!
should remain constant at T( n) during the eourse of
disease. We would expect the proportion of infected
cells to increase exponentially as the virus replicates.
We would also expect the proportion of infected cells
actively producing new virus to increase as well. I will
consider this next.
To model the increase in the proportion of infected
cells, we use the same data as before and construct a
pair of simultaneous difference equations,
T(n + 1) = T(n) - l~T;(n) + r(n)
and
T;(n) = G+ j3(n»T(n)
Here the function j3 represents the increase in the
proportion of infected cells as n increases. We clearly
must have
o ~ j3(n) ~ ~
The logic behind these equations is straightforward .
The first represents the T cell count in total after n
days. It says that the total is the previous day's total
minus the cells killed by HIV + the response (addi-
tional cells) that the body produces because of the
infection. Equation 2 represents the total number of
infected cells. j3 is assumed to increase from 0 to asi
n increases. At this stage the growth of j3 has not been
specified. So Equation 2 describes the rate of increase
in the proportion of infected T cells.
It is here that the problems with the hypothesis that
HIV takes ten years to cause AIDS become apparent. If
HIV is actively replicating we would expect the num-
ber of cells infected to increase exponentially. This
will drastically increase the speed of disease progres-
sion. Indeed this is what you would expect in a normal
viral disease (the numbers will be different, though).
A replicating virus should rapidly cause a disease if
it causes a disease at all. Exponential increase in j3,
which is what would be expected for viral replication,
implies that
where 1 represents the rate at which the total proportion
of infected cells is increasing.

If we assume for simplicity that r( n) = 0, then we
find
T(n + 1) = (1 - 1600 + Hl- rn»T(n)
We can easily work out the behaviour of T( n) by
iteration. We can pick different values of r to describe
possible rates of increase in the number of infected
cells. Here are some possibilities.
1. r = .9975
T(100) = .713T(0)
T(200) = .439T(0)
T(300) = .241T(0)
T(730) = .008T(0)
2. r = .99
T(I00) = .592T(0)
T(300) = .101T(0)
3.r =.9
T(167) = .199T(0)
T(365) = .027T(0)
4. r = .85
T(162) = .199T(0)
For all values of r :::; .99 the value of T( n) drops
below 20% of its original value after between 160
and 175 days. So what this model predicts is in stark
!
contrast to what is observed. If of the T cells in
the lymph glands are infected with HIV initially, and
the infection spreads so that the proportion of infected
cells increases exponentially as would be expected for
a replicating virus, then 80% of an infected person's
T cells will be lost after 160-170 days. Addition of
response functions such as we tried above will not
significantly delay the decline in the number ofT cells.
If we try a logarithmic decline of the form employed
above, then a problem develops. The actual behaviour
of the disease depends crucially on the value of r(O).1f
r(O) = .15T(0), then after 10 years, the body has lost
only 35% of its T cells. A slightly higher value sees
the number of T cells rise substantially. After 600 days,
there would be twice as many T cells as initially if we
took r(O) =
.05T(0). This behaviour is not tenable
either.
We also need to take into account the possibility
that the number of actively replicating cells is greater
than 1% of the infected cells. What we find is that the
93
disease progression speeds up dramatically. If instead
of 1% we have 3% replicating then we would have
T(n + 1) = (1 - 160(! + ~(1 - rn»)T(n) + r(n)
Even with a logarithmic decline in the number of
new cells created as response to the infection, this
produces a much faster decline in T cell numbers. Tak-
ing
.0IT(0)
=
r(n) (1 + logn)
then the number of T cells in the body drops to only
5% of its original level after 200 days, clearly a much
faster rate of progression.
The conclusion that must be reached after this anal-
ysis, incomplete and rather simple though it is, is that
it is very difficult to see why a large number of infected
cells actively replicating takes so long to cause a dis-
ease. For all the plausible alternatives tried here, the
disease progression is rapid. Indeed, if we acknowl-
edge the possibility that the number of actively replicat-
ing viruses increases as the disease progresses, which
is likely, then the killing ofT cells should pickup speed
as the disease progresses. A rigorous analysis would
surely predict that it is simply impossible for a virus,
actively replicating and present in large numbers, to
take years to cause disease. Such a virus should cause
disease quickly or not at all. So we must question the
claim that HIV is present in large quantities at all stages
of disease, active, and still takes 10-12 (or even more)
years to produce AIDS in an HIV + person.
Section 2 Quantitative Competitive PCR
In 1993 Piatak et al. also claimed to have employed a
technique called Quantitative Competitive Polymerase
Chain Reaction to detect very large quantities ofHIV-
1 RNA in blood plasma in HIV+ individuals. The
basis of the technique is that in order to quantify the
amount of HIV in a sample (the 'wild type HIV'), a
control which differs from the wild type only by a
small internal deletion is amplified competitively with
the wild type by PCR. After a certain number of PCR
cycles, the ratio of wild type to control can be calcu-
lated and knowledge of the initial amount of control
present allows estimation of the total amount of wild
type in the original sample. The method is based upon
the assumption that the ratio of wild type to control
remains a constant throughout the cycle. Justification
for this is that the wild type and the control differ only
94

by a small internal deletion and so the amplification
efficiency for both should be the same. Therefore the
ratio should remain constant.
The replication of any sample in PCR is essentially
a random event (Brock et al., 1994). A strand of DNA
can either replicate or not replicate. So we have a
process that is governed by the binomial probability
distribution. Piatak et al. 's paper is notable for a lack of
error analysis. It is not my purpose here to provide one,
but rather to suggest a method by which the problem of
errors may be addressed. This method suggests that the
QC-PCR technique is highly suspect. Results obtained
from it should be treated with extreme caution.
Let the amount of wild type (which we will call X
for convenience) initially present in the sample be N
molecules. And let the amount of control (Y) present
be M molecules. So the ratio initially is
M -InN -In (g(1 + Pi))
K= N
I wish to examine how this ratio can change after
n PCR cycles. Let the ratio after n cycles be Kn.
Clearly
Dn(Y)
Kn = Dn(X)
Dn (X) and Dn (Y) are the amount of derived prod-
uct for X and Y respecti vel y after n cycles. If the relati ve
efficiency of PCR for X at the ith cycle is Pi and the
relative efficiency for Y is qi, then we have
n
Dn(X) = TI(I +Pi)N
i=1
and n
Note I have not assumed that Pi =
qi. The reason
for this is that because we have a binomial probability
distribution for PCR replication, we cannot say that
the efficiencies at each cycle for X and Yare identical.
In other words, it is not necessarily true that the same
proportion of X and Yare replicated each time. To see
this, consider an experiment when we have N 5=
and M = 2, with probability! for replication of any
strand of DNA. The possibilities for DI (Y) are 2, 3
and 4, with probabilities, t, t
! and respectively. For
DI (X) we could have either 5, 6, 7, 8, 9 or 10 strands
of X type DNA, with probabilities tz, f2, f2
~, and
tz respectively. Clearly we would expect the ratio
D1(Y)
D1(X)
to differ from the original ratio. In fact, if X is present
in greater quantities than Y originally then we might
expect the ratio Dn(Y) to Dn(X) to decrease at each
cycle. However, the precise behaviour which would
occur is far from clear. I intend to analyse the various
possibilities in later work.
The purpose at hand now is to estimate the value
of Kn relative to K. This is not difficult:
Taking the natural log of Kn yields
InKn = InM+ln(g(I+qi))
Using the fact that the log of a product is the sum of
=
the individual logs (In ab In a + In b) we obtain
In Kn = In -M ~ (1 + qi)
+ L...J In -:-----"--:-
N i=1 (1 + Pi)
Inverting we find that
~ (l+qi)
Kn = Kexp L...Jln (1 .)
i=1 + P.
The assumption used by Piatak et al. is that if the
average replication efficiency of X and Yare the same,
then the ratio ofthe derived products will be the same.
We see here that K = Kn if and only if 1 + Pi = 1 + qi
for each i. But we cannot assume this. The fact that the
average replication efficiencies are equal, which itself
is an unproven assumption, only means that
n n
L:(I + Pi) = L:(I + qi)
;=1
The example noted above indicates that even when
the probability of replication for X and Yare identical
at each cycle we cannot assume that the actual replica-
tion efficiencies, that is the proportion of the samples
actually replicated, are identical at each cycle, simply
that on average, the two efficiencies will be equal.
This formula for Kn allows us to derive an expres-
sion for the error in the estimate for the size of X based
upon our preexisting knowledge of the size of Y. If
K = M / N, then clearly N = M / K. But our estimate

for N the amount of wild type (X) present is going to
be M / "'n. Thus if we write the true value of the size
of X as tr(X) and the estimate es(X), then we easily
see that we must have:
tr(X) = exp tIn (1 + qi)
es(X) i=1 (1 + Pi)
It is clear from this that small variations in the
relative efficiencies of replication can lead to enormous
variations in the estimate for the size of X. For example,
if we assume that Pi = =
P for all i and that qi q for all
i (conditions unlikely to be met in practice), then our
estimate for the error reduces to
tr(X)
es(X)
= (1 ++ Pq)n
1
Piatak et ai. used 45 PCR cycles. If we let
=
(1 + q)/(1 + p) .909, so the replication of the wild
type overall happens to be 10% more efficient than that
of the control, then we will overestimate the true size
of the wild type by a factor of 72. If the replication
efficiency in a particular process is 20% more efficient
for the wild type then we overestimate the amount
present by a factor of 3600. It is, of course, possible
that we could underestimate the true value enormously
as well. However, if the wild type is originally present
in excess of the control, then it seems likely, although
it is not clear without detailed calculations of the pos-
sible outcomes, that the replication of the wild type
would tend to be slightly more efficient. This would
mean that typically we would be overestimating our
sample size. The reason that one might expect the wild
type replication to be slightly more efficient is that if
95
the replication probabilities (note that the efficiency of
replication is not identical to the actual efficiency at a
given cycle) of X and Yare the same at each cycle and
there is more of X than Y, then the probability that the
amount of X increases in that particular cycle is greater
than the probability that the size of Y increases. This
suggests that the most likely outcome at each cycle
would be a decrease in the ratio of the size of Y to the
size of X. This needs to be checked by detailed calcu-
lations which I have not attempted here. Regardless of
this, it is clear that a great deal more work on the actu-
al efficiencies of the PCR process are necessary before
results obtained through QC-PCR can be treated with
confidence.
References
Brock, T.D., M.T. Madigan, J.M. Martinko & J. Parker, 1994. Biol-
ogy of Microorganisms. Prentice Hall International Editions.
Duesberg, P.H., 1989. Human immunodeficiency virus and acquired
immunodeficiency syndrome: Correlation but not causation.
PNAS U.S.A. 86: 755-764.
Embretson, J., M. Zupancic, J.L. Ribas, A. Burke, P. Racz, K.
Tenner-Racz & A.T. Haase, 1993. Massive covert in fection
of helper T lymphocytes and macrophages by HIV during the
incubation period for AIDS. Nature 362: 359-362.
Pantaleo, G., C. Graziosi, J.E Demarest, L. Batini, M. Montroni,
C.H. Fox, J.M. Orenstein, D.P. Kotter & A.S. Fauci, 1993. HIV
infection is active and progressive in lymphoid tissue during the
clinically latent stage of disease. Nature 362: 355-358.
Piatak, M. Jr., M.S. Saag, SJ. Clark, J.C. Kappes, K.C. Luk, H.
Halen, G.M. Shaw & J.D. Ufson, 1993. High levels of HIV-I in
plasma during all stages of infection determined by competitive
PCR. Science 259: 1749-1754.
Root-Bernstein, R., 1993. Rethinking AIDS: The tragic cost of pre-
mature consensus. Free Press.
P. H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 97-104, 1996. 97
© 1996 Kluwer Academic Publishers.

HIV as a surrogate marker for drug use: a re-analysis of the San Francisco
Men's Health Study

Bryan J. Ellison I, Allen B. Downey2 & Peter H. Duesbergl

1Department of Molecular and Cell Biology, 229 Stanley Hall, University of California, Berkeley, CA 94720, USA
2EECS Computer Science Division, 387 Soda Hall, University of California, Berkeley, CA 94720, USA

Received 31 January 1994 Accepted 17 June 1994

Abstract

Our analysis of drug use and morbidity data from a cohort of 1034 men yields the following results: 1) HIV infection
is a strong indicator of drug use - HIV-positive respondents reported an average lifetime dose of recreational drugs
(excluding marijuana) 2.3 times higher than HIV-negative respondents. 2) Homosexuality is a strong indicator
of drug use - homosexual respondents reported an average lifetime dose 2.0 times higher than heterosexual
respondents. 3) The incidence of AIDS-defining diseases was not limited to respondents infected with HIV, but
was almost completely limited (98%) to respondents who reported using drugs. We also address a previous report
(Ascher et aI., 1993) that was based on the same database and purported to show that HIV alone correlates with
the development of AIDS. Specifically, we show that the relationship between HIV infection and CD4+ T Cell loss
is weaker than reported by Ascher et al., and provides little evidence for a causative relationship. These results
support the hypothesis that long-term, habitual drug use can cause the conditions known as AIDS (independent of
the presence ofHIV), and refute the hypothesis that HIV alone causes these conditions independent of drug use.

Introduction AIDS hypothesis and for a drug-AIDS hypothesis. The

A Nature Commentary by Ascher et al. purported to
show that infection by the human immunodeficien-
cy virus (HIV) alone correlates with the development
of the acquired immune deficiency syndrome (AIDS)
(Ascher et aI., 1993). According to their analysis of
the San Francisco Men's Health Study (SFMHS), drug
use had no effect on T cell loss over time, while all
cases of AIDS and all T cell depletion occurred among
HIV-positive men. Ascher et al. interpret this apparent
correlation between HIV and AIDS as support for 'the
well-established causal relationship between HIV and
AIDS' (Ascher et aI., 1993).
The power of the statistical tests Ascher et al. use is
often insufficient to justify the conclusions they draw.
This paper will discuss the deficiency of these tests. In
some cases, however, the absence of a detailed descrip-
tion of the methods they used made it impossible for
us to verify their results.
Ascher et al. also selectively cited existing lit-
erature on the debate over AIDS etiology, ignor-
ing a wealth of evidence arguing against the HIV-
molecular and epidemiological inconsistencies of the
HIV hypothesis include the inability of the virus to
induce AIDS in chimpanzees and the existence of HIV-
free AIDS cases (Duesberg, 1992; Duesberg, 1993a).
There is ample evidence that alkyl nitrites, recreation-
al drugs primarily used by male homosexuals at risk
for AIDS, and related compounds produce irreversible
immune suppression and pneumonia in mice after
long -term exposure, and that the nitrites follow a dose-
dependent relationship with the incidence of AIDS in
humans (Holt et aI., 1979; Haverkos, 1988; Newell,
Spitz & Wilson, 1988; Ortiz & Rivera, 1988). Cocaine
and heroin, moreover, have long been associated with
severe immune deficiencies in humans, independently
of HIV infection (Duesberg, 1992).
In addition to reviewing the data cited by Ascher et
ai., we were also able to perform our own analysis of
the primary data. This paper presents some of our find-
ings. Despite the extremely sparse reporting of AIDS
indicator diseases in the database, we found 45 cases of
these diseases among HIV negative respondents. Also,
we quantified a higher level of drug use among HIV
98
positive men than among their my negative counter-
parts. These results suggest a direct link between drug
use and AIDS independent of my infection.
The SFMH Study
The SFMHS is a population-based longitudinal survey
of 1034 men, recruited in 1984 from the San Francis-
co precincts most heavily populated with homosexual
men. (For reasons unknown to us, Ascher et al. used
only 1027 of these men in their analysis). Of these
subjects, 816 identified themselves as homosexual or
bisexual and 215 as heterosexual. At the end of the
study's seventh year, 578 men remained my nega-
tive, 46 had seroconverted, 400 had entered the study
already seropositive, and 10 remained undetermined;
215 men had been officially recorded with diagnoses of
AIDS. Data are collected by semi-annual interviews,
which tabulate such self-reported data as medical con-
ditions, use of pharmaceutical or recreational drugs,
and a number of other responses that are difficult to
verify.
The SFMH Study, however, was not designed to
test for the cause of AIDS. my was presumed from
the beginning to be the etiological agent, so that no
attempt was made to account for the inherent prob-
lems of self-reported answers, nor for the preceding
years of unrecorded drug use (especially among my-
positives). Inadequate records were also kept of spe-
cific AIDS diseases and of drug use patterns occurring
during the course of the study.
We shall document these and other defects of the
SFMHStudy as well as of the Commentary by Asch-
er et al. based on that study. Our analysis will show
that Ascher et al. 's claim that 'the population-based
SFMHS provides a rigorously controlled epidemiolog-
ical model for the evaluation of aetiological hypothe-
ses' is unjustified (Ascher et al., 1993).
The Ascher et ell. Commentary
The Commentary reported a perfect association
between my and AIDS, as well as between my and a
progressive decline in CD4+ T cells. It also found no
relationship between drug use and T cell loss. But the
analysis suffers from several logical flaws:
1) The mY-based clinical definition of AIDS is
circular, because it fails to report AIDS-defining con-
ditions in the absence of my infection. Conventional
Table 1. mY-negative AIDS diseases (578 total mY-negative
men).
AIDS diagnostic disease Number(%)
Salmonella 18 (40)
Non-pulmonary tuberculosis I (2)
Thrush!oral candidiasis 6 (13)
Immune thrombocytopenic purpura (ITP) 2 (4)
Herpes zoster 9 (20)
<200 CD4+ T cells 14 (31)
total 45 (100)
Single condition 40 (89)
Double condition 5 (11)
diseases such as pneumonia or tuberculosis are only
reclassified as AIDS in the presence of antibodies
against mY, or on the presumption of infection (Insti-
tute of Medicine and National Academy of Sciences,
1986; Centers for Disease Control, 1987; Centers for
Disease Control and Prevention, 1992). Ascher et at.
imply they have taken all such diseases into account.
The Commentary notes 'Duesberg has also argued that
the case definition of AIDS is 'circular' and that my-
seronegative AIDS cases are excluded by definition. In
the SFMHS, AIDS cases were diagnosed by the clini-
cal criteria defined by the Centers for Disease Control
(CDC), which are irrespective of my infection sta-
tus.' (Ascher et aI., 1993). However, ourreview of the
SFMHS database indicates that for the first five years
of the study, respondents were only asked whether they
had been diagnosed with AIDS or Kaposi's Sarcoma,
not whether they had been diagnosed with any of the
AIDS indicator diseases. In the latter part of the study,
the surveys included questions about some AIDS indi-
cator diseases, but in total more than two-thirds of the
data about these diseases is missing.
2) my infection and drug use have been shown
to correlate with one another. Risk behaviors for virus
transmission, including extreme sexual activity and
sharing of injection equipment, generally involve use
of such recreational drugs as heroin, cocaine, alkyl
nitrites, and others (Jaffe et at., 1983; Newell, Spitz &
Wilson, 1988; Schechter et at., 1993). For this reason
any epidemiological study of my infection must care-
fully control for drug use. The authors compare drug
use among the homosexual or bisexual respondents and
the heterosexual respondents, using sexual preference

as a proxy for serostatus. They thereby imply that there
is no difference in drug use between HIV positive and
HIV negative respondents. According to Ascher et al.,
'Except for amyl nitrite ... the percentage of subjects
reporting heavy use of each drug was similar in both
sexual preference groups.' (Ascher et al., 1993). While
heterosexuality is an effective proxy for HIV-negative
serostatus (all but one of the heterosexual respondents
was HIV-negative), homosexuality is not a reasonable
proxy for HIV-positive serostatus (almost half of the
816 homosexual respondents were HIV-negative). Our
analysis (below) shows that there is a significant cor-
relation between drug use and serostatus.
3) The hypothesis of drug use as the cause of AIDS
is analogous to the cigarette-smoking hypothesis of
lung cancer and the alcohol hypothesis of liver cirrho-
sis (Lauritsen & Wilson, 1986; Duesberg, 1992). That
is, disease symptoms depend primarily on the lifetime
dose of the relevant drug, a function of both quantity
and number of years of consumption. Thus a proper
longitudinal study would quantify each respondent's
total lifetime drug use. Ascher et aI. imply that they
have done this: 'We examined the cohort at 6-monthly
[sic] intervals for 96 months, and obtained drug-use
data and determined HIV serostatus at each examina-
tion' (Ascher et al., 1993). But in the Commentary, all
study subjects were stratified according to a single drug
use report, taken during the first wave of the study. Fur-
thermore, although the respondents were asked about
use of nine to ten different psychoactive drugs (see
below), only four of those drugs were incorporated
into the paper's analysis. Moreover, no mention was
made of AZT, the toxic and immune-suppressive DNA
nucleoside analogue prescribed as AIDS therapy.
Our analysis of the data and our results
Statistical tests are based on Cochran and Cox t-
tests (with unequal variances), or on univariate linear
regression.
AIDS without HIV
Clinically, AIDS is defined entirely in terms of about
30 conventional diseases presumed to have been com-
paratively rare in 20- to 55-year-old men before 1980.
If a patient with one or more of these indicator diseases
tests positive for HIV antibodies, he is usually diag-
nosed with AIDS. The AIDS case definition has been
expanded several times by the CDC, each time adding
99
new diseases to the diagnostic list. The 1987 CDC defi-
nition incorporated some two dozen diseases, and was
the universal standard for diagnosis until January 1,
1993, when five new conditions were added (Centers
for Disease Control, 1987; Centers for Disease Control
and Prevention, 1992). As of 1992, 390/0 of the AIDS-
defining conditions reported in the United States were
not diseases of immunodeficiency, including Kaposi's
sarcoma, several lymphomas, dementia, and wasting
disease (Centers for Disease Control, 1993).
Despite the absence of most of the relevant dis-
ease data, we found 45 HIV-negative men with AIDS-
defining conditions (according to the CDC), as listed in
Table 1. Of those, 34 qualified under the older (1987)
definition; 11 qualified only under the 1993 definition,
having either <200 CD4+ T cells or thrombocytope-
nia. Fifteen of the 45 were reported in the first round
of interviews in 1984. Many HIV-negative men were
followed up only inconsistently thereafter or were lost
altogether, and were therefore inadequately monitored
for AIDS diseases. Given the missing data on many
of the study subjects and on other potential AIDS-
defining conditions, this must be taken as a minimum
estimate.
At least eight of these cases were published a few
years earlier by Winkelstein and other researchers
with the SFMHS (Lang et aI., 1987). The earli-
er study also included as many as 133 other cases
of AIDS- or early-AIDS-related symptoms, such as
lymphadenopathies, persistent rashes, wasting con-
ditions, or histories of worsening herpes infections.
This earlier paper, and our finding of HIV-free
AIDS indicator diseases, undermine the claim of Asch-
er et aI. that 'No cases of AIDS ... have been record-
ed among these [seronegative] men' (Ascher et al.,
1993).
The relatively high incidence of opportunistic dis-
eases listed in Table 1, found in men recruited between
the ages of 25 and 54, is particularly revealing, for
such conditions would normally not be expected to
occur among the healthiest age group in the popula-
tion. The presence of these diseases indicates some
non-HIV factor at work. It is important to emphasize
that had any of these 45 men been positive for antibod-
ies against HIV, they would likely have been recorded
as AIDS cases.
An analysis of the 'no drug use' subgroup
A second question arose over the figure displayed in
the Commentary. One of the six longitudinal T cell
100
Table 2. Average age, AIDS vs. non-AIDS.
mv negatives
Number Mean age (std)
AIDS condition 45 37.7 (7.3)
No AIDS disease 533 34.6 (7.1)
Age difference 3.1 years
t-test p-0.OO5
curves purported to describe mY-positive men report-
ing 'no drug use'. The authors' criteria for this classifi-
cation were based on self-reported use of four drugs-
marijuana, cocaine, nitrites, and amphetamines - dur-
ing the two years prior to the beginning of the study.
We examined the database to find the subjects who
met these criteria, and inspected these men's recorded
answers to check whether they remained a truly drug-
free control group, looking at all other drugs and at
AZT.
That 'no drug use' curve was apparently based on
twenty seropositive men in the database who reported
no use of the four drugs upon entry. Of these men,
one reported using a different drug (downers) immedi-
ately prior to entry, five others admitted using various
drugs (marijuana, nitrites, cocaine, and hallucinogens)
at later times during the study; thirteen reported taking
AZT. After accounting for overlaps, this left only three
of the original twenty who claimed to be completely
drug-free, at least during the study. One of these men
showed a sharp decline in CD4+ T cell counts during
the first two years of the study, was diagnosed with
AIDS, developed a Pneumocystis carinii pneumonia,
and died months later. The remaining two individuals
appear not to have declining T cell counts, and neither
was diagnosed with AIDS or died.
Even if the 'no drug use' group were well-defined,
it would still be inappropriate to present a simple aver-
age ofT-cell counts, especially, as in the Commentary,
without providing error bars to indicate the variation
within the group. First, an individual's T-cell count
varies widely over time, making time-series data of
this kind dubious. Secondly, not all subjects participat-
ed in all waves; thus the 'group' represented at each
wave is made up of different respondents. Finally, the
use of unnormalized T-cell counts weights individuals
with naturally high T-cell count more than individuals
with naturally lower counts. The unreliability ofT-cell
mv positives
Number Mean age (std)
204 35.5 (6.4)
195 34.0 (5.9)
1.5 years
p-0.020
counts as a measure of the health of the immune sys-
tem is well-known; averaging this data over ill-defined
and varying groups does not help - it only obscures
whatever conclusions might be drawn from individu-
al trends. Figure 1 shows the T-cell counts for each
of the 20 'drug-free' subjects over time. Any decline
in the average T-cell count in this group is primarily
due to a single individual with an unusually high and
sharply-declining T-cell count. Generalizations about
the health of the members of this group on the basis of
this chart would be entirely unjustified.
Drug use as a correlate ofHN infection and AIDS
The SFMHS database suffers several shortcomings
that limit its ability to test the drug- and mv-
hypotheses of AIDS. Because many of the drug-use
questions were not answered by many of the subjects
at various times throughout the study and all drug data
were self-reported and unverified, it was difficult to
construct a reliable measure of lifetime drug use. Nev-
ertheless, we were able to convert data about frequen-
cy of drug use into an estimate of total doses, and to
integrate this data over time into an estimate of total
lifetime dose. For example, if an individual reporting
annual use of a drug was assigned one dose unit, anoth-
er individual reporting weekly use would be assigned
52 dose units.
Data were available from fourteen semi-annual sur-
veys; we added a fifteenth data point representing the
eighteen months preceding the beginning of the study.
Drug use was condensed into two indices for each indi-
vidual- the total combined drug use reported over the
8.5 years (marijuana, nitrites, cocaine, 'crack' cocaine,
amphetamines, hallucinogens, uppers, downers, ethyl
chloride, heroin, and 'other '), and a similar index with-
out marijuana. The category' crack cocaine' was added
in wave 10, at which point the category 'other' was no
 101

2000.,-----,.....--------------, among homosexual and heterosexual respondents. It

confirms the role of mv as a surrogate marker for
drug use. mY-positive men on average used 128%
more drugs (ignoring marijuana) than did the mv-
...
II)

C negative subjects (the difference is statistically signif-

::I
0
u icant). Moreover, the drug use data from later in the
Qi study contradict the claim of Ascher et aZ., based only
u 1000
+ on drug data from the first survey, that drug use is
V
0
u similar among homosexuals and heterosexuals. Table
iO 3 shows that homosexuals used twice as many drugs
::I
'0 as the heterosexuals (again ignoring marijuana), a sta-
~
'0
.!:
tistically significant difference. Use of nitrite inhalants
was particularly heavy among homosexuals, and AZT
0 (naturally) was used almost exclusively by mv posi-
0
2 3 4 5 6 7 tives respondents (Ascher etaZ., 1993).
Among mY-positive subjects, we looked for a dif-
time (years)
ference in total lifetime drug use between respondents
who had been diagnosed with AIDS and those who had
not. Contrary to our expectations, we did not find a sta-
1.200
.......
tistically significant difference. The statistical power of
............ _------------ the test was limited by some of the problems we have
1.000 mentioned above, as well as the following:
a) Associations between drug use and AIDS are
c:::I obscured by the likelihood that by the time an indi-
.,.8 800
o
vidual develops serious illness, he will begin to
() reduce his drug use. In order to demonstrate this
"0
"*::I 600
effect, we compared the level of drug use reported
=g ;::------....
......... _- ...................
by respondents who used AZT before and after they
'"0>
~ 400
~
--- began AZT treatment. Average drug use before
AZT treatment is 169% higher than after (26.4 ±
1.3 before versus 9.84 ± 1.3 after, p = 0.0001),
- Seronegative· no drug use
200 moderate drug usa suggesting that recreational drug use declines when
--OOroPOS.NO. ~:~i~ patients become ill.
o rl guss b) If the drug hypothesis is correct, respondents who
heavy drug use
developed AIDS during the course of the study,
1986 1988 1990 especially during the first few years, must have
used drugs prior to the beginning of the study. Table
Fig. 1. (top) Individual T-Cell counts of 20 HIV-positive respon-
dents reporting no drug use during the study. (bottom) In the Com- 2 shows that men reporting AIDS or AIDS diseases
mentary, Ascher et al. average these curves and present the resulting were significantly older than other mY-positive
smooth line without error bars (Ascher et aI., 1993). They attribute respondents. This discrepancy indicates that our
the downward trend in that line to HIV-infection, rather than to the
estimates of lifetime drug dose are less accurate
sharp decline of a few individuals.
for the respondents who developed AIDS, because
more of their lifetimes fall outside of the study.
c) Much of the drug use data is missing from the study
longer used in our analysis, so that only ten drug cat- altogether. Only 17% of the respondents answered
egories were examined for any given wave, and AZT all drug use questions during the first seven years;
was not included in the analysis. Thus we used data 22 % of the respondents answered half or fewer of
from up to 150 drug responses gathered from each the questions. Furthermore, there is a strong neg-
individual (15 waves times 10 drugs each). ative correlation between reported level of drug
Table 3 compares the mean lifetime dose of drugs use and number of responses to drug use ques-
among mY-positive and negative respondents and tions (slope = -1.76 ± 0.32, P < 0.0001), meaning
102
Table 3. Average doses of drugs (other than marijuana) per year, mv+ vs. mv-
and homosexuals vs. heterosexuals.
Number Mean± SE
mv+ 400 29.7 ± 2.8
mv- 578 13.0 ± 1.2
Ratio 2.28
I-test p-O.OOOI
that those subjects who responded the fewest times
claimed the highest average drug use. This result
indicates that men using the most drugs were least
reliable in their responses.
Conclusions
The Ascher et al. Commentary was a faulty analysis
of the SFMHS database:
a) Because of the authors' dependence on the circular
CDC definition of AIDS, they ignored the inci-
dence of AIDS indicator diseases among the mv-
negative respondents. One consequence of their
artificially perfect association between mv and
AIDS is that all other correlations between risk
factors and AIDS are obscured.
b) By failing to quantify the enormous difference in
drug use between mY-positives and -negatives,
they overlooked this potential explanation of the
greater decline in CD4+ counts among mv
antibody-positive men.
c) By stratifying subjects according to a single drug
use report, they included users of recreational drugs
and AZT in their 'no drug use' group, and were able
to ignore the problem of missing data later in study.
d) By failing to analyze the data with and without
marijuana they allowed some drug associations to
be obscured or minimized. Study subjects reported
large amounts of marijuana use, which numerically
tended to drown out reported use of more powerful
drugs. The general willingness to admit marijuana
use may reflect the lesser degree of social stigma
attached to this particular drug. In any case, mari-
juana is less cytotoxic than other drugs examined in
the study (such as nitrites [Haverkos & Dougher-
ty 1988]), and is likely to be insignificant in the
etiology of AIDS.
Number Mean± SE
Homosexual 816 22.8 ± 1.5
Heterosexual 215 11.7 ± 2.6
1.94
p-0.OOO2
e) T cell counts provide a questionable marker of
AIDS progression, especially in the SFMHStudy.
For one thing, several important AIDS-defining
diseases do not result from immunodeficiency;
Kaposi's sarcoma, for example, has been described
in homosexual men without measurable immune
deficiencies (Murray et aI., 1988; Spomraft et at.,
1988; Friedman-Kien et aI., 1990). Furthermore,
the individual T cell counts recorded in the database
often fluctuated greatly with time, and the aver-
age T cell curves (not reproduced here) showed
major irregularities that Ascher et ai. smoothed out
with some undescribed adjustment (Fig. 1). Final-
ly, many CD4+ counts were missing throughout
the study, apparently for individuals who could not
be contacted at various waves. The average T cell
curves therefore reflect a constantly changing sub-
set of men over time.
Furthermore, the SFMHS database may be inad-
equate to test drugs, mv, or any other agent as a pro-
posed cause of AIDS:
a) Of the 446 men who were seropositive after seven
years, only 46 had seroconverted at known times
during the study; the other 400 had been infected
at unknown times preceding the study.
b) AIDS-defining diseases were poorly monitored.
The SFMHStudy relied at times on self-reported
answers rather than medical records and only
inquired about a changing and severely incompIete
list of those diseases. Many of the men were fol-
lowed up inconsistently after the first six months,
which may explain the observation that 15 of the
45 cases of AIDS indicator diseases among mv-
negative respondents were recorded during the first
wave.
c) No data about drug use exist for most of the years
preceding the study, so that it is impossible to quan-
tify lifetime drug consumption. Without more reli-
able data on lifetime drug use, no controlled anal-

ysis of drug-AIDS associations is possible in this
cohort.
Nevertheless, some conclusions can be drawn from
the SFMHStudy. Perhaps most significant of these
is our finding of 45 HIV-free cases of CDC-defined
AIDS diseases. These can be added to the list of
nearly 5000 cases of HI V-free AIDS-defining diseases
and immunodeficiencies already uncovered in at least
75 references in the existing literature (compiled in
a review paper) (Duesberg, 1993a). The seronega-
tive AIDS conditions have been found primarily in
the same risk groups as seropositive AIDS, including
central Africans, male homosexuals, intravenous drug
users, and hemophiliacs.
The association between drugs and AIDS-defining
diseases in this database appears to be greater than the
association between HIV and AIDS. AIDS conditions
were reported among 260 men, 215 of whom were
infected with HIV - a total of 82%. Of the same group,
93% admit using drugs other than marijuana, a total of
96% including marijuana, and a total of 98 % including
both marijuana and AZT.
The most compelling argument against the drug
hypothesis of AIDS would be the existence of a group
of drug-free, HIV-positive AIDS cases, but such could
not be found in the SFMHS. On the other hand, the
strongest argument against the virus-AIDS hypothesis
would be a group of drug-using, HIV-negative AIDS
cases, which may indeed exist in the SFMHS cohort
(see above).
Further results might possibly still be extracted
from the SFMHS database, including an analysis of
the effects of AZT; of the 400 seropositive men in the
study, 215 (54%) reported use of this DNA chain-
terminating chemotherapy. But an epidemiological
study of the causality of AIDS, controlling for both
HIV and lifetime drug exposure, will require some
other more adequate cohort. From the standpoint of
biological plausibility, the toxicity of long-term drug
use makes much more sense as a damaging agent to the
immune system than do the 'enigmatic mechanisms' of
the conventional retrovirus HIV (Ascher et al., 1993).
Acknowledgements
We are indebted to Warren Winkelstein, Jr., for pro-
viding access to the data from the SFMHS study, and
to Eric Vittinghoff for technical assistance. We also
thank Phillip Johnson, Richard Strohman, Malcolm
103
Zaretsky, John Lauritsen, Charles A. Thomas, Steve
Smale, and Harvey Bialy for critical reviews. Sup-
ported in part by the Council for Tobacco Research,
USA, and private donations from Glenn Braswell (Los
Angeles, Calif., USA), Dr. Richard Fischer (Annan-
dale, Va., USA), Dr. Fabio Franchi (Trieste, Italy) and
Dr. Friedrich Luft (Berlin, Germany).
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in mice chronically exposed to amyl nitrite. In: Health Hazards
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Le & M.V. O'Shaughnessy, 1993. HIV-l and the aetiology of
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© 1996 Kluwer Academic Publishers.

A critical appraisal of the Vancouver men's study

Does it refute the drugs/AIDS hypothesis?

Mark Craddock
School of Mathematics, University of New South Wales, Sydney, Australia

Everyone who eats a tomato dies

Abstract

The Vancouver cohort study of Schechter et al. (1993a) claiming to refute the drugs/AIDS hypothesis made by
Peter Duesberg is critically examined. It is argued that the data as reported do not refute the Duesberg theory.
Further, the data may in fact be taken as experimental confirmation of the drugs/AIDS hypothesis. It is concluded
that research needs to be done so that the drugs/AIDS hypothesis can be correctly tested, and that the Vancouver
research group should release more of its data so that a proper evaluation of their results can be made.

Introduction usage in a given population and make a prediction of

In the March 13, 1993 issue of the Lancet, a report by
a team from Vancouver, Canada headed by Dr. Martin
Schechter was published. This study purported to show
that HIV has a crucial role in the aetiology of AIDS, and
to refute a hypothesis proposed by Dr. Peter Duesberg
that many AIDS diseases are caused by long term abuse
of recreational drugs and the use of AZT. This claim
will be examined with two questions in mind: 1) Does
the Vancouver study adequately address the Duesberg
hypothesis from a sound methodological basis and 2)
do the data presented by Schechter et al., when given a
correct statistical analysis, support their conclusions?
We will see that the answer to both questions is clearly
no.
Methodology
In order to successfully test a theory, it is necessary
to correctly formulate that theory. Otherwise, any data
that are obtained cannot be properly evaluated. When
we examine the Duesberg hypothesis we see that what
has been claimed is that the use of recreational drugs,
notably nitrite inhalants, AZT and various prescribed
drugs, is the true cause of certain AIDS defining dis-
eases. If this is to be tested a model needs to be for-
mulated. The model must address the level of drug
the number of AIDS diseases that we expect in that
population over time. An analogy may be made with
cigarette smoking and cancer.
The claim that cigarette smoking is a primary cause
of lung cancer must be formulated on a dose/rate
basis. Given a population of people smoking (say) 40
cigarettes a day, we need to predict the number of cases
of lung cancer a year in the population. The prediction
should be based upon both medical and actuarial con-
siderations. We then compare the rates of occurrence
of lung cancer in a population which smokes heavi-
ly with the rate in a population that does not smoke.
We consider our hypothesis to be true, that smoking
causes lung cancer, if the incidence of lung cancer in
the smoking population is near that predicted, and the
incidence in the non smoking population is essentially
zero.
Clearly if the drugs! AIDS hypothesis is to be test-
ed, a similar model based upon actuarial data must be
formulated. From these data we must develop a predic-
tion which can disentangle the roles of HIV and nitrites
in AIDS aetiology. The basic methodological flaw in
the Vancouver study is that it includes no such model
to begin with. Thus their results cannot be checked
against any prediction for verification or refutation. If
we do not know what we are looking for, we will not
recognise it when we find it.
106
Let us now review briefly the contents of the report
as it appeared in the Lancet. The team studied 715
homosexual men in Vancouver, Canada and measured
changes in CD4 counts over time, and checked for
diagnoses of AIDS defining illnesses. The study was
divided into two arms. One consisted of 237 men who
were HIV 4- when the study began and 128 who sero-
converted during the time of the study. The other arm
consisted of 350 men who were HIV - during the entire
time the study was conducted.
The report found that there were 136 cases of AIDS
defining diseases in the seropositive group and no
AIDS diseases in the seronegative group. Moreover,
it was claimed that as both arms in the study had
significant levels of drug use, then if the Duesberg
hypothesis were correct, there should have been AIDS
diseases occurring in the seronegative group as well.
As none were observed, the hypothesis that drug abuse
is crucial to AIDS rather than HIV status was refut-
ed. In addition, the levels of CD4 cells in seropositive
patients who did not develop AIDS was said to have
steadily declined, whereas in the seronegative group
the CD4 count was stable over 10 years.
However, in the absence of a proper model for the
drugs/AIDS hypothesis, the claim that ithas been refut-
ed is not a valid one. The Vancouver report does not
state the level of drug use in both arms. Since we are
dealing with a toxicological model, the precise drug
dosage is crucial. If we study nitrites as a cause of
AIDS diseases, then we would expect that those dis-
eases due to nitrites would occur in the group most
heavily using nitrites. If it is the case that the seropos-
itive arm had heavy nitrite use and the seronegative
arm light use, then the drugs/AIDS hypothesis would
predict that the diseases associated with nitrites would
appear in the seropositive arm, and not the negative.
This is precisely what was observed. Consequently,
the Vancouver study might be taken as evidence for
some version of the drugs/AIDS hypothesis. That is
why drug dosage is crucial.
The Vancouver report states that drug use was quan-
tified as never versus ever. It made no attempt to verify
drug use by other means, which would have been diffi-
cult. The logic used by the team was as follows: since
drug use took place in both arms of the study (88%
of patients in the seropositive arm admitted to using
nitrites versus 56% of the seronegative group), then
AIDS diseases should occur in both arms. They only
occurred in the HIV+ arm. Therefore the development
of AIDS diseases must be dependant upon HIV status.
But this logic is false.
To begin with, as Peter Duesberg pointed out in a
letter to the Lancet (Duesberg, 1993) what matters is
the quantities of drugs that were used. It is known that
risk behaviour correlates with HIV seropositivity. This
is stated in the report (p 658). Since the 350 seronega-
tive men remained seronegative, then their actual prac-
tice of risk behaviour, including nitrite use, must have
been low. We would thus expect that nitrite use in
the seronegative arm would be significantly lighter
than the seropositive arm. Any reasonable model of
the drugs/AIDS hypothesis would thus predict fewer
AIDS cases in the seronegative arm.
Now consider the actual experimental situation as
described by Schechter et al. If we are looking at
nitrite use as a cause of AIDS, then we are study-
ing a seropositive group of 321 men who used nitrites
at least once, and a seronegative population of 196
who did so. Already we have a significant difference.
But the situation is clearer if we look at Schechter
et al.'s response to Duesberg's criticisms. They state
(Schechter, 1993)
'[in the seronegative arm] 78 ... reported recre-
ational drug use at everyone of their study visits.
... of the 78 men, 71 reported regular use of nitrite
inhalants, and their mean dose intensity, derived
from each subject's average over the entire follow
up period, was 21 uses per month (range 1-143)'
This information changes once more our analysis
and contains an important statistical point (see below).
First, we know that of the 196 HIV-men who reported
use of nitrites, only 71 used it regularly. Therefore in
any model of the nitrites/AIDS hypothesis we would
expect to see AIDS diseases apparing in these 71 men.
Clearly we are now looking at a significantly different
situation. We are not comparing AIDS diseases in a
population of 365 with one of 350. We are comparing
AIDS diseases in a popUlation of up to 321 with a
population of 71.
Statistical considerations
There is a further problem with this which is not imme-
diately apparent. The distribution quoted here is a tail
distribution, or a skewed distribution. For tail distribu-
tions the mean is not the best measure that is available
(Raj, 1968). The most appropriate measure in this con-
text is the median, but this is not given. (We are also
told nothing about the level of drug use on a dosage
basis in the seropositive arm).

The problem with a tail distribution is that it
is impossible to determine from the mean the true
behaviour of data points being measured. To explain
this remark in the context of the Vancouver study,
observe that a mean of 21 for 71 people implies a
total use for the entire group of 1491 times per month.
But we are told that the range of use was 1 to 143. If
we subtract the number 143 from 1491, we find that
70 people used nitrites 1348 times per month, giving
an average use of 19. However, if we subtract the left
hand endpoint 1 from 1491, we have 70 people using
nitrites 1490 times per month, an average of 21.2 times
a month. Thus removal of the left hand endpoint causes
the average to rise! This is why the average for such a
group is not a useful measure. So the statement that the
71 individuals had a 'mean dose intensity' of 21 times
a month is one with little content.
Note further that we can distribute nitrite use in
many different ways in our group of 71. For example,
if 61 men used nitrites once a month, and 10 used
them 143 times a month, then this gives a total of
1491 times a month with mean 21 for the group. It is
entirely possible that we have in this group 5 or 6 men
who used nitrites about 140 times per month and 65
who used it occasionally, say 8 or 9 times a month.
It is therefore crucial that the Vancouver team release
more information on just what the true nitrite usage in
the seronegative group was.
The next problem we have is how to properly study
a tail distribution. The way this is done in correct sam-
pling theory is by oversampling extreme points (Raj,
1968). What this means is that in order to properly
evaluate the effects of nitrite usage in the seronegative
arm, we need disproportionately large numbers of peo-
ple in the same using nitrites once or twice a month, and
using them 143 times a month. The Vancouver study
does not meet these criteria. If it did the mean would
be higher than 21. The reason for this is that we know
the total nitrite usage was 1491 times per month, but
only 10 people using nitrites 143 times per month will
produce that level of usage. Consequently, if the end-
points had been oversampled, the total nitrite usage
for the group would be much higher. The seronega-
tive nitrite users have not beenproperly sampled from
a statistical point of view; th~s, any conclusions we
attempt to draw from this sample will be of dubious
validity.
Now let us consider the problem once again of what
a proper model of the drugs/AIDS hypothesis would
actually predict. In the seropositive arm 136 AIDS
diseases occurred. This is out of a total of 365 patients,
107
or 37% (in passing we note that this seems to be less
than the HIV/AIDS hypothesis predicts). But if we
are restricted to those who used nitrites, we have 136
cases out of 321, or 42%. We are not told the levels of
nitrite use in this arm, or whether all the AIDS cases
in this group used nitrites. However, on request from
the Lancet a further set of data is available. This shows
that ofthe people who developed AIDS diseases, 88%
had used nitrites, and 75% had used illicit drugs such
as LSD, heroin, MDA and cocaine (Schechter et at.,
1993b).
Given that between 37% and 42% of the nitrite
users developed AIDS, and being a little conservative,
as a first guess we might postulate that one third of the
heavy nitrite users in a given population will develop
AIDS diseases after ten years of use. If we apply this
model to the seronegative arm, then we see that if all 71
nitrite users were heavy users then we would expect 24
AIDS cases in this group. But we know that this is not
our true situation. We may have as few as six or seven
heavy users, a few moderate users, and the majority
light users. Then our model would predict two AIDS
cases.
This is the crux of the problem with the Vancouver
report. We might expect as few as two AIDS cases
in the seronegative arm. Without knowing how many
seronegative men were heavy nitrite users, we really
cannot make a prediction and so cannot draw a con-
clusion. Clearly it makes no sense to draw a conclu-
sion based on the fact that no AIDS cases appeared
when you expected two. This would be like rejecting
the claim that cigarette smoking causes lung cancer
because you know six heavy smokers who have not
yet developed the disease. This appears to be what the
Vancouver group have done.
Of course the very simple model for the
drugs/AIDS hypothesis presented here is not to be tak-
en too seriously. The point being made is that a definite
model must be formulated if we are to properly test the
hypothesis that nitrites cause AIDS diseases.
Other criticism
By concentrating on nitrite use it is clear that the Van-
couver study does not adequately address the role of
drugs in AIDS diseases. Of course nitrites are not the
only drug. A proper toxicological model of disease
causation in AIDS must consider all the drugs being
taken and attempt to associate them with certain dis-
eases. For example in the Vancouver study, one of the
108
AIDS patients developed dementia. It might be pos-
tulated that dementia is caused not by nitrite use, but
by abuse of LSD. We must therefore know the lev-
els of LSD use in both seropositive and seronegative
arms so we can estimate the number of dementia cas-
es expected. Indeed, since AIDS is really a collection
of 29 diseases, we should formulate a theory for each
particular disease that can be adequately tested.
The most important drug, one ignored by the Van-
couver study, is AZT. Clearly this was not used by the
seronegative arm at all. AZT became available to AIDS
patients in Canada with a CD4 count less than 200 in
1987. In 1989 it became available to HIV+ asymp-
tomatic individuals. A crucial part of the Duesberg
hypothesis is that AZT is 'AIDS by design' (Dues-
berg, 1992). Since the hypothesis is that AZT is caus-
ing AIDS diseases, then it is necessary to have data
on AZT use in the seropositive arm in order to evalu-
ate this drug's role. However, the Vancouver study is
silent on the use of AZT. We do know that Schechter
et at., in reply to Duesberg, states that 19 patients who
reported no drug use had an average fall in CD4 count
of 138 per year before 1986. After this AZT became
available, which is why 1986 was chosen as the cut
off point. This implies that people in the Vancouver
study began using AZT in 1987. Failure to adequately
address AZT use is a serious omission.
We are also told nothing of the general history of
the seronegatives and seropositives in terms of their
general health. Schechter et at. state that there were 6
non AIDS deaths in the seropositive arm: two cases of
hepatitis, one lung cancer, one homicide, one suicide
and one drug overdose. In the seronegative arm there
were only two deaths: one suicide and one myocar-
dial infarction. These numbers are small but they raise
questions about the general health of both groups. For
example, what was the incidence of hepatitis in both
groups? We have two deaths due to hepatitis in the
seropositive arm, none in the seronegative. What was
the incidence of sexually transmitted diseases in both
groups? And there was also one drug overdose in the
positive arm. How many intravenous drug addicts were
there in the seropositive arm? These are just some of
the questions that the Vancouver study raises.
The Vancouver data
The Vancouver study states that frequency of recepti ve
anal intercourse was fixed at 25% of sexual encounters
to determine an approximately equal division. This is a
very odd statistic to define. It is not clear what is actu-
ally being measured by it. In the seroincidentarm, 82%
of the men reported that 25% of their sexual encoun-
ters involved receptive anal intercourse. This naturally
correlates with the number of men who used nitrites in
that group (88%). But we are not told how often these
men had sexual encounters. Someone having one sexu-
al encounter per month will use less nitrite to facilitate
anal intercourse than someone having hundreds of sex-
ual encounters a month.
Now let us turn to the question of CD4 decline. It is
here that some more interesting questions arise. Of the
19 non drug using patients mentioned by Schechter et
at. (remember also that drug use was unverified), they
state that up to 1986, their average CD4 decline was
138/pLlyear. Now we are told that 95% of the 19 had
an average fall between 7 and 269 a year. Again we
have a huge range of values (also 95% of 19 is 18).
So one patient must have had an average fall of less
than seven. 18 times 138 is 2484. So this group had
an average fall of 24841pLlyear. 269 is 11 % of 2484.
So one patient accounted for 11 % of this total decline.
Of course this is the same problem we had above. We
are not told the median which is the correct (useful)
measurement for a distribution of this type, and so
we have no way of knowing what the real picture is.
If you remove one patient with an average decline of
2691pLlyear, the average for the rest of the group falls
to 130. Removal of a patient with a fall of 71 pLlyear
causes the average fall for the remaining 17 to rise
to 146lpLlyear. This begs the question: how many of
these non drug using individuals (of course the whole
analysis turns on whether we believe these patients)
had statistically significant falls in their CD4 counts
over the 2-4 years up to 1986? We know at least two
patients had falls averaging 7 or less. What this means
is that for one patient, his CD4 count was 28 less at his
1986 visit than his 1984 visit. Is this a meaningful fall?
Could this not be accounted for by natural variations in
CD4 count? Without more information these numbers
are essentially useless.
We are also told that of the 78 seronegative men
who reported drug use at each follow up visit, there
was no significant fall in CD4 count. 95% had a final
count in the range of 875 to 1017 . We are also told that
none of these men ever had a CD4 count less than 300.
This obviously implies that some ofthe men had counts
near 300 at some time. Now if these 78 men werefor the
most part not using drugs, then the drugslAIDS hypoth-
esis would imply that we would not expect many of
them to have significant falls in their CD4 count. Since

95% of78 is 74, then four men lay outside the range of
875-1017 in their CD4 counts. Now the formulation of
the drugs/AIDS hypothesis given above was that about
113 of heavy users of nitrites would develop AIDS after
about ten years. If it turns out that four of the seroneg-
ative group had CD4 counts near 300 at some stage,
and that about 12 of the 78 were heavy nitrite users,
then this data could be taken as experimental confir-
mation of this version of the drugs/AIDS hypothesis.
The reason for this is that AIDS diseases are postulated
to develop because of immune deficiency. If an HIV+
individual had a fall in CD4 count from (say) 900 to
just over 300, this would be taken as evidence that the
person was developing AIDS. So by this argument, if
four heavy nitrite users had falls in their CD4 counts
from a high level to around 300, then they could also
be said to be progressing to AIDS. Of course, we are
not told anything about these men.
A graph showing the falls in CD4 count over time
of seronegative and seroincident men is presented on
page 659 in the Lancet study. This graph contains some
important information that is obscured by its presen-
tation. The graph shows that the CD4 count in the
seropositive men who did not use nitrites at the last
study visit ranged between approximately 400 and 750.
The graph misleadingly is connected by lines passing
through the mean for the group at each study visit.
Since we have another tail distribution here, this pro-
cedure is invalid.
Note that only 15 of the seroincident men never
used nitrites. Note also that some of these 15 men on
their first study visit after seroconversion had a CD4
count around 750. Thus in the non nitrite using arm of
the study, there seems to have been very little decline
in CD4 count over time. We are told that the average
decline in CD4 count in the seroincident group based
on linear regression was 50 cells per year. The final
mean CD4 count was 547 in the seroincident group.
This is lower than the mean for the seroincident group,
which reported to nitrite use. It seems that the fall
in CD4 count in the seroincident group was almost
entirely concentrated in the nitrite using group. The
non nitrite users seem to have a virtually static CD4
count, with probably a few having significant falls.
Another interesting question arises over the graph
on page 659 and Schechter et al.'s claim that no
seronegative individual ever had a CD4 count less than
300. As stated above, this implies the existence of a
seronegative individual who had a CD4 count near 300
at some stage, possibly as many as four such people.
But these individuals have been left off the graph. The
109
error bars on the seronegative side of the graph imply
that no patient ever had a CD4 count less than 800 in
this group, but the statement by Schechter et al. clear-
ly refutes this. If they had been included in the graph,
then the error bars would have shown some mv-
men with a CD4 count lower than any of the HIV+
men. It would be interesting to know the justification
for leaving this man or men out of the data set for the
graph.
There is another peculiarity here in the figures. It is
stated that in the seroincident arm the final average T
cell count was 547. Then we are told that n = 25 and
the range was 414-680. Now of the 136 AIDS cases
in the seropositive arm, 35 were in the seroincident.
So 93 seroincident men had not developed AIDS by
the time the report was written. We know that some of
the individuals in the seroincident arm (the non nitrite
users) had a final CD4 count of about 750. Clearly
these individuals were not included in the 25 on whom
the calculation of the average 547 was based. So the
question is: how were these 25 men selected? Were
they all in the nitrite using arm?
Now let us look at the figures on drug use in the
patients who did develop AIDS diseases. As noted
above, 88% ofthe men in seropositive arm who devel-
oped AIDS diseases admitted to nitrite use. 75% admit-
ted to use of other drugs such as heroin and cocaine.
We also know that one seropositive individual died
from a drug overdose. So we may wonder how many
of the seropositives were actually drug addicted. But
the data on drug use here is telling. Of the 136 men
who developed AIDS, about 120 admitted to nitrite
use. Many of these must also have used drugs such
as heroin, LSD, cocaine, MDA, and speed. There are
many other drugs that were not tested for in this group.
In fact, it is possible that every single one of these
patients had heavy illegal drug use if the 75% is not
totally included in the 88%. Moreover many of these
patients, quite possibly all, will have been treated with
AZT. Therefore it seems that not only is HIV corre-
lated with the development of AIDS diseases, so is
the use of illegal drugs. This is what the drugs/AIDS
hypothesis actually says.
The drugs/AIDS hypothesis states that those with
the heaviest long term drug usage are the ones who
will develop AIDS diseases (leaving aside the natural
incidence of these diseases, of course, and the inci-
dence of these diseases in other immunocompromised
people, e.g. transplant patients). Most and possibly all
of the AIDS patients in this study had records of heavy
drug use. The fact is that at least 63% of them had used
110
at least two types of drugs and many possibly more.
In the seronegative individuals who did not develop
AIDS diseases, far fewer reported ever having used
nitrites regularly, and far fewer used other drugs. None
used AZT. Most of them hardly used drugs at all, and
most of those who did must have used them far less
frequently than the seropositive men who developed
AIDS. Moreover in the seropositive arm, those who
never reported nitrite use had a much lower decline in
their CD4 count, and some seem to have had no decline
at all.
The conclusion from this is clear. The Vancouver
study found that drug use was highly correlated with
AIDS development and immunological impairment.
Indeed, it may be even more strongly correlated with
these than HIV itself. It is not possible to draw that
conclusion directly from the data as presented, but it
is suggested. A full analysis of the Vancouver study
data may very well provide experimental confirmation
of the drugs/AIDS hypothesis. It certainly provides
evidence that drug use is at the very least a cofactor for
HIY. Curiously, in their report Schechter et ai. do not
mention the possibility that drugs may be a cofactor.
It would be interesting to know if they feel that their
data are not indicative of drugs like nitrites having a
role in the development of some diseases like Kaposi's
Sarcoma.
Conclusion
The Vancouver study seeks to refute the drugs!AIDS
hypothesis. A detailed analysis of the data that
Schechter et ai. supply clearly shows this to be untrue.
The study fails because it does not set out to test a
realistic model of the theory it is supposedly testing.
It thus violates a basic tenent of experimental science.
Moreover, the actual data seem to show a strong corre-
lation between both the development of AIDS diseases,
immunological disfunction and the abuse of nitrite
inhalants. This correlation seems to be at least as strong
and possibly stronger than the correlation with HIV
infection. It is therefore important that the Vancouver
group release more information on questions such as
levels of nitrite use and AZT use in the seropositive
arm. And most importantly, a rigorous toxicological
study of the effects of nitrites and AZT on animals
must be carried out. This will supply the evidence
necessary for the proper formulation of a model of
the drugs/AIDS hypothesis that can then be rigorously
tested.
Acknowledgements
The author wishes to thank Dr. Steffanie Strathdee of
the Vancouver Study Team.
References
Duesberg, P.H., 1993. HIV-I and the aetiology of AIDS. Lancet 341:
957.
Duesberg, P.H., 1992. AIDS acquired by drug consumption and other
noncontagious risk factors. Pharmacol. Ther. 55: 201-277.
Raj, D., 1968. Sampling Theory. McGraw Hill.
Schechter, M.T., KJ.P. Craib, J.S.G. Montaner, T.N. Lee, M.V.
0' Shaugnessy & K.A. Gelmon, 1993a. HIV-1 and the aetiology
of AIDS. Lancet 341: 658--659.
Schechter, M.T., K.J.P. Craib, J.S.G. Montaner, T.N. Lee, M.V.
O'Shaugnessy & K.A. Gelmon, 1993b. Aetiology of AIDS.
Lancet 341: 1222-1223.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 111-125,1996, 111
© 1996 Kluwer Academic Publishers.

Duesberg and the right of reply according to Maddox-Nature

Peter H. Duesbergl & Harvey Bialy2

1Dept, Molecular and Cell Biology, UC Berkeley, Berkeley, CA 94720, USA
2BiolTechnology, 65 Bleecker Street, New York, NY 10012, USA

In 1993 John Maddox, the editor of Nature, commis- References

sioned a commentary refuting the hypothesis that drugs
cause AIDS (Ascher et ai., 1993). The piece described 1. Ascher, M.S., H.w. Sheppard, W. Winkelstein Jr and E. Vit-
tinghoff, 1993. Does drug use cause AIDS? Nature (London)
215 patients each of which had used drugs (Duesberg, 362: 103-104.
1993a; Duesberg, 1993b; Duesberg, 1993c). In view 2. Duesberg, P., 1993a. Aetiology of AIDS. Lancet 341: 1544.
of this Duesberg sent a letter to Nature arguing that the 3. Duesberg, P., 1993b. HlV and the aetiology of AIDS. Lancet
perfect correlation between drug use and AIDS con- 341: 957-958.
4. Duesberg, P.H., 1993c. Can epidemiology determine whether
firmed, rather than refuted, the drug hypothesis. Mad- drugs or HlV cause AIDS? AIDS-Forschung 12: 627-635.
dox censored the letter and wrote an editorial 'Has 5. Maddox, J., 1993. Has Duesberg a right of reply? Nature
Duesberg a Right of Reply?' (Maddox, 1993). The (London) 363: 109.
editorial pointed out that the world's oldest science
journal could not afford an open scientific debate on
the cause of AIDS because of the perceived dangers of
infectious AIDS.
In an editorial on January 19, 1995, Maddox
promised to lift the censorship to give 'Duesberg and
his associates an opportunity to comment' on two
Nature studies that in his opinion prove the HIV-AIDS
hypothesis.
In the following we document how Maddox-
Nature honors its commitments. Our documentation
includes
(i) photocopy of Maddox's News and Views article of
January 19, 1995,
(ii) summary of phone conversation between Maddox
and Bialy, on January 12, 1995,
(iii) our letter to Maddox and commentary on the two
new Nature studies,
(iv) Maddox response to our commentary,
(v) our third letter to Maddox published by Nature
with editorial comments, on May 18, 1995,
(vi) our letter to Maddox stating that Nature's com-
ments are erroneous.
(vii) Nature's final letter.
112
Duesberg and the new view of HIV
This Journal has offered Dr Peter Duesberg and his associates an opportunity to comment on last week's publications
suggesting that the Immune system reacts hyperactlvely to HIV Infection.
THE publication last week of two important
articles on the dynamics of the infection of
people by HIV is agreed to have been a
important landmark in the process of under-
standing the disease called AIDS, but not
everybody will be aware of that. Reporting
of the event has been curiously selective. In
particular, the British newspaper The Sun-
day Times, which as recently as a year ago
was replete with accounts of how HIV can
have little or nothing to do with the causa-
tion of AIDS, chose not even to mention the
new developments in last Sunday's edition.
Is it planning a major account of how it
came to be so misled, thus to mislead its
readers? Or is it waiting for a sign from
Professor Peter Duesberg, ofBerkeley, Cali-
fornia. who started the hare the newspaper
followed eagerly for two years?
The reasons why the new developments
are (or should be) an embanassment for
Duesb~are simply put. AIiUost frOm the
outset 0 DS as a recognized disease in the
early 1980s, the objective index of an in·
fected person's state of health has been the
concentration in the blood ofT lymphocytes
carrying the CD4 antigen. The more ad-
vanced the infection, the smaller the con-
centration of CD4' cells.
But Dueiberg was guic~ to point to a.
~ in the observations: although the
concentration of CD4' cells might decline
with the persistence of infection, ~
no dramatic increase of the frequency of
infected T cells as infection gave way to
overt disease. Cell i1kth by inter-cellular
infection could hardly be consistent with
that state of affairs.
In essence. the new developments re-
solve the paradox by showing that the T
cells in an infected person's blood are likely
to have been created only in the few days
previously. There will not have been time
enough for more than a small proportion of
them to have become infected. while those
that harbour virus will be killed off Very
soon. So the scarcity of T ceUs from which
virus can be recovered in test-tube experi-
ments IS consistent With the assertion that
the immune system.s 111 overdrive from the
onset of infection b HIV.
On this (new view, the progressive de-
cline of the CD4+ concentration with the
duration of infection is rather a symptom of
the underlying infection than the crux of its
mechanism. What seems to matter is that
there should be cells (including T cells)
somewhere in the body (the lymph nodes are
likely candidates) from which virus parti-
cles continue to h::ak into the blood plasma.
NATURE . VOL 373 . 19 JANUARY 1995
News and Views article in which John Maddox invites 'Peter Duesberg and his associates' to comment on new findings concerning HIV and
AIDS which were recently publislied in Nature. The specific points addressed by Duesberg and Bialy in their reply are underlined.
In other words, Duesberg is right to have
argued all along that the usuall¥ slow de-
cline of CD4~ cells IS not consistent with
<what one would expect from a specific
cytotoxjc viral mechanism. The explana-
tion is that the CD4' population in the blood
at any time has been freshly created.
Despite this journal's severe line, some
months ago, on Dueserg's right of reply to
critics ofhis position, it is now in the ge~eral
interest that his and his associates' views on
the new developments should be made pub~ •
lic. Duesberg was not available to take a
single telephone call one day last week, nor
able to return it, but one of his associates
appeared to welcome the idea of a comment
on the articles by Wei el af. and Ho et af.
(Nature 373,117-122 & 123-126; 1995).
That will be eagerly awaited and will be
published with the usual provisos - that it
is not libellous or needlessly rude, that it
pertains to the new results and that it should
not be longer than it needs to be.
Meanwhile, one important question
stands out like a sore thumb: why, after more
than a decade of research, has it only now
emerged that the response of the immune
system to infection by HIV is hyperactivity
rather than the opposite? Simon Wain-
Hobson, writing in News and Views last
week (Nature 373, 102; 1995), remarked
that the investigators were able to reach
their start1ing conclusions "by teaming up
with mathematicians".
Intuitively, the sharp recovery of CD4'
cells in the first few days after the adminis-
tration of antiviral drugs pointed to their
rapid production by the immune system.
But in retrospect the good fortune of the
investigators is clear. Only with the advent
of highly specific drugs directed against
HIV was it possible to cut off viral produc-
tion so abruptly that the decline in plasma
viraemia could fonn the basis for a model of
viral production. New techniques for assay-
ing the low levels'of virus involved were
also necessary; had the drugs been available
only a few years earlier. these studies would
have been impossible on that account.
In retrospect, the dynamics of the im-
mune system would seem to be central to
any consideration ofthe body's response to
infection. by measles virus as well as HIV.
And modelling of such processes as the
production of lymphocytes (B as well as T
cells) in the immune response shou ld be a
relatively easy task (compared with, say. the
appearance of endless molecular species in
the evolution of a molecular cloud).
To be sure, immunologists are no stran-
NEWS AND VIEWS
gers to quantitation in this spirit. And the
involvement of mathematicians is simply
explained by the authors' desire to be sure
that even experts in this area approved of
their data analysis. But the rarity of such
studies says something depressing about the
state of biology, for all its modernity. De-
spite the explosion in molecular knowledge
(including molecular knowledge ofviruses),
the information to perform this kind of quan-
titative modelling is almost never available.
In this case, the relevant data have emerged
only after a decade of intensive research,
fuelled by intense public interest in a most
unpleasant pathogen. But virology is not the
only field in which biology would benefit
from more quantitative methods.
What more is to come? Now that the
basis for the low CD4' T-cell count in AIDS
patients is clear. further studies of the viral
dynamics will be eagerly awaited. How
much virus is produced by each produc-
tively infected cell? How fast is the virus
produced by the lymph nodes? And what is
responsible for lcilling the CD4' T cells? If
these last are indeed being destroyed by the
CDS' cells of the inunune system, as Wain-
Hobson suggests (and this remains to be
seen), it will undoubtedly lend further sup-
port to the idea that individuals who are
repeatedly exposed to HIV while remaining
unaffected are protected by their cytotoxic
T lymphocytes (Rowland-Jones et af., Na-
ture Medicine I, 59-41; 1995).
The search for effective antiviral therapy
will also benefit. Already Wei el af. have
followed the emergence of mutants resistant
to one drug, and studies of others, alone and
in combination, will surely follow. Here
too, improved quantitation of the size of
viral pools in different tissues, and their
respective replication rates, will be vital.
What does this mean for basic research
on AIDS, the cause eloquently advocated a
year ago by Dr Bernie Fields (No lure 369,
95; 1994)? Wei el af. and Ho el af. have
provided the basis for a much more pointed
programme of investigation from which. no
doubt, a complete picture ofthe dynamics of
this hitherto perplexing disease will emerge.
A return to basics seems already to have
happened. The prospects oftherapy are much
more difficult to tell, but has a fuller under-
standing ever failed to deliver improve-
ments of technique? The danger for the
Duesbergs of this world is that they will be
left high and dry. championing a cause that
will havt;ever fewer adherents as time passes.
Now may be the time for them to recant.
Jo~n Maddox
189

Summary of phone conversation between John Maddox and Harvey Bialy
on January 12, 1995
On the afternoon of January 12, the day the nature issue
containing the Ho and Wei et at. papers appeared, and
one day after the press conference announcing these
landmark publications, I received a rare telephone call
from my colleague, the newly knighted, Sir John Mad-
dox, editor of nature. The essence of the ensuing con-
versation is summarized below.
After congratulating John on his recently acquired
honorific, I asked to what did lowe the pleasure
of his call. He then asked me what I thought of the
'HlV-1 dynamics' papers. I replied by thanking
him for publishing them, as they were so trans-
parently bad, they would convince any reasonable
scientist who had the endurance to read them that
the HlV-AlDS hypothesis was absolutely intellec-
tually bankrupt. I also chided him by saying that
even Wain-Hobson didn't know what to make of
them, judging by his incoherent news & views piece
that accompanied their publication.
To my surprise, his response to these remarkes was
remarkably devoid of any outrage. We discussed
in a cursory manner some of the obvious criticisms
of the papers, such as their lack of controls, and the
methodological and biological problems with their
estimates of free infectious virus. I also mentioned
that I thought it ironic that after years of denying
that T cells turned over at the rate of 5% in two
days, the HIV-AIDS protagonists were now at last
admitting this well known fact. He responded by
asking how did I explain the "dramatic increase in T
cells after treatment with the protease inhibitor". I
replied that this transient, hardly dramatic, increase
was also a well known phenomenon called lympho-
cyte trafficking, which occurs in response to many
chemical insults.
113
The conversation then changed direction and John said
that he had, without success, been trying to reach Peter
(Duesberg) to inform him that he was, in this instance,
willing to rescind his previous 'refusal of the right
of reply' and would welcome a correspondence from
Peter (and myself) addressing what we perceived as the
shortcomings ofHo and Wei et al. He promised me that
if the piece was relevant, succinct and not personally
rude, he would publish it 'unslagged'. When I asked
him what this meant, he said that it would be pub-
lished as received, without prior review and without a
response appearing in the same issue. I said 'do you
mean it will be allowed to generate its own replies?',
and he said yes. I congratulated him on his willingness
to open a proper scientific debate, and said I would
communicate our conversation to Peter.
I was a bit surprised to see his editorial in the fol-
lowing week's nature in which he went much further
than our conversation in offering the pages of nature
to uncensored debate. I was, however, not surprised
to discover, some weeks later, that the response which
appears unedited in this monograph, was deemed 'too
long by half and too unfocussed' to warrant publication
in his own highly esteemed journal.
114

February 7, 1995

Sir John Maddox

Nature, Macmillan Publishing
4 Little Essex St.
London, WC2R 3LF
England

Dear John,

As per your invitation, published in News and Views "Duesberg and

the new view of HIV", and your invitation to Harvey Bialy over the phone,
"to comment on last week's publications" by Wei et al. and Ho et al. we
submit "Responding to 'Duesberg and the new view of HIV'" by Duesberg &
Bialy. We are delighted that after years of editorials, News & Views, and
letters and censored letters we have been invited at last to make our case in
our own words.
As you can see, our report meets your criteria of "not libellous or

needlessly rude, that it pertains to the new results and that it should not be
longer than it needs to be". The length of our commentary is compatible with
the results presented in the two papers covering 10 pages, and the challenges
delivered by the two accompanying News & Views from you and Wain-
Hobson.
We both respect your courage and integrity to undertake an
uncensored debate on the HIV-AIDS hypothesis.

Best regards

Peter Duesberg
Harvey Bialy

PS 1\ hard .:I)py is in the mail. We can send a disc if that helps.


Responding to 'Duesberg and the new view of mv'*
Peter H. Duesbergl & Harvey Bialy2
IDept. Molecular and Cell Biology, UC Berkeley, Berkeley, CA 94720, USA 2BiolTechnology, 65 Bleecker Street,
New York, NY 10012, USA
The editor of Nature, John Maddox, has issued a pub-
lished invitation to 'Peter Duesberg and his associates
... to comment' on two new studies by Wei et al. (1)
and Ho et al. (2) that he feels lend strong support to the
hypothesis that HlV causes AIDS (3). Maddox credits
us for having identified two paradoxes of this hypoth-
esis, (i) 'Duesberg was quick to point to a paradox ...
[that] there was no dramatic increase of the frequency
of infected T-cells as infection gave way to overt dis-
ease', and that (ii) 'Duesberg is right to have argued
all along that the usually slow decline of CD4+ cells
[T-cells] is not consistent with ... a specific cytotoxic
viral mechanism' (3).
According to Maddox, 'the new developments
are (or should be) an embarrassment for Duesberg',
because they 'resolve the paradox'. But we do not
see any reason why a scientist should be embarrassed
for having pointed out paradoxes in the past, which
ever way these paradoxes are subsequently solved. We
also object to rhetoric personalizing a scientific debate.
However, it is embarrassing that in the name of science
clinical, public health, journalistic, and political deci-
sions have been made in the past, based on a hypothesis
that - we all agree now - was unproven at that time.
Since the HlV-AIDS hypothesis makes many
assumptions that are paradoxical, if not bewildering,
for pre-HIV virologists, and since the new studies do
not clearly define the HlV hypothesis, we shall first
state the hypothesis and then explain why, in light of
these 'new' studies, it remains paradoxical.
In 1984 it was proposed that the retrovirus HlV can
cause such diametrically different diseases as Kaposi's
sarcoma, pneumonia, dementia, diarrhea, and weight
loss (4, 5). All of these diseases and over two dozen
more are now collectively called acquired immuno-
"Revised version (see 7 March letter from Duesberg and Bialy
to Maddox).
115
deficiency syndrome (AIDS) (6), if antibody to HlV
is present. But many of these diseases, including
Kaposi's sarcoma, lymphoma, dementia and weight
loss, are neither consequences of, nor consistently
associated with immunodeficiency (7, 8). For example
Kaposi's sarcoma and dementia have been diagnosed
in male homosexuals whose immunesystems were nor-
mal (9-13). As a cause of these diseases HlV was pro-
posed to follow an entirely unprecedented course of
action:
1) HlV was proposed to cause immunodeficiency by
killing T-cells. But retroviruses do not kill cells
(14, 15).
2) Within weeks after infection, HlV would reach
moderate to high titers of 10--104 infectious units
per ml blood (16), sufficient to induce antiviral
immunity and antibodies (a positive 'AIDS-test').
According to Shaw, Ho and their collaborators,
HlV activity is 'rapidly and effectively limited'
by this antiviral activity (17, 18). Prior to antiviral
immunity, HlV would neither kill T-cells nor cause
AIDS (16, 19). But all other viruses are primarily
pathogenic prior to immunity; the reason vaccina-
tion protects against disease. Not one virus exists
that causes diseases only after it is neutralized by
antiviral immunity (20, 21).
3) On average 10 years after HlV is neutralized, the
virus is postulated to cause AIDS diseases (5,22).
But all other viruses typically cause disease within
days or weeks after infection, because they repli-
cate exponentially with generation times of 8 to
48 h (20, 23, 24).
4) As a consequence of antiviral immunity, the virus
titer is typically undetectably low prior to and even
during AIDS (25-29). Only in rare cases HlV titers
are as high as in the asymptomatic, primary infec-
tion (16, 30). But in all other viral diseases the virus
116
titer is maximally high when viruses cause disease
(20,21).
5) Antiviral immunity would typically restrict HIV-
infected lymphocytes to less than 1 in 500 - prior
to and even during AIDS (14, 26, 27, 30-32). But
all other viruses infect more cells than the host can
spare or regenerate when they cause disease (20,
21).
6) The hypothesis fails to shed any light on the cau-
sation of non-immunodeficiency AIDS diseases,
like Kaposi's sarcoma, dementia, lymphoma and
weight loss which make up 39% of all American
AIDS cases (8, 33).
Today this HIV-AIDS hypothesis stands unproven
and has failed to produce any public health benefits
(34-36).
The new studies are claimed by two News and
Views articles from Maddox (3) and Wain-Hobson (43)
to resolve the paradoxa, (I) how HIV kills T-cells, (II)
how HIV causes AIDS, and (III) why HIV needs 10
years to cause AIDS. But we argue that the new studies
have failed to resolve any of these paradoxa, in fact
they have added new ones:
(I) How HlV kills T-cells. Until HIV appeared on the
scene, retroviruses did not kill their host cells. This is
the reason they were considered possible tumor virus-
es. Since retroviruses integrate their genes into the
chromosome of the host, they can only replicate as
long as the host survives integration and remains able
to express integrated viral genes. Therefore a cytocidal
retrovirus would be suicidal. Indeed, HIV proved to be
non-cytocidal. It is mass-produced for the "AIDS-test"
in immortal T-cells in culture at titers of 106 infec-
tious units per ml (37, 38). Luc Montagnier and others
have confirmed that HIV does not kill T-cells (39-42).
Hence the claim that HIV causes AIDS by killing T-
cells is paradoxical.
The new papers have indeed resolved this paradox
by shifting the paradigm: According to Maddox, T-
cells 'that harbour virus will be killed off very soon'
- but not by HIV - by the immune system. Also con-
sistent with a non-cytocidal virus, Wei et at. report
that 'the average half-life of infected PBMCs [periph-
eral blood mononuclear cells] is very long and of the
same order of magnitude as the half-life of uninfected
PBMCs'. But, paradoxically, the same investigators
also report that 'the life span of virus-producing cells
is remarkably short (tI12 = 2 ± 0.9 days)', although
these cells are in the same system as their long-lived
HIV-infected peers (1). Ho et al. state that 'there is
virus- and immune-mediated killing of CD4 lympho-
cytes' (2). But, according to the News and Views article
by Simon Wain-Hobson, 'an intrinsic cytopathic effect
of the virus is no longer credible' (43).
It is consistent with this 'new view of HIV' that
there is no correlation between virus titers and T-cell
counts in the patients that Wei et at. and Ho et al. have
studied. In some of Ho et al.' s patients, i.e., # 303 and
# 403, a 100-fold variation in virus titers corresponds
to no changes in T-cell counts. In Wei et al.s patients
100-fold variations in virus titers correspond to only
0.25 and 3-fold variations in T-cell counts - hardly a
correlation to prove that HIV kills T-cells.
Since HIV is no longer viewed as a T-cell killer, the
above paradox is solved. However, if T-cell killing via
antiviral immunity were the cause of AIDS, we would
have a bigger HIV-AIDS paradox than before. Since
only 1 in 500 T-cells are ever infected, and most of
these cells contain latent HIV not making viral proteins
(25,26,30,44), only less than 1 in 500 T-cells could
ever be killed by antiviral immunity.
(II) How HIV causes AIDS. Until HIV appeared
on the scene, the pathogenicity of a virus was a direct
function of the number of virus-infected cells: the more
infectious virus there was, the more cells were infected,
and the more pathogenic an infection was.
But in typical AIDS patients HIV is so rare, that
even leading AIDS retrovirologists from the US, like
Robert Gallo, and the UK, like Robin Weiss, failed for
years to isolate HIV from AIDS patients (45,46). Like-
wise, virus-infected cells are so rare that they could not
be found by George Shaw, the senior investigatorofthe
new study by Wei et al., Gallo and their collaborators
in most AIDS patients (27) - until the rare proviral
DNA could be amplified with the polymerase chain
reaction (PCR) (31, 44, 47).
Although the new studies never mention the per-
centage of infected T-cells, Maddox confirms the status
quo: 'the scarcity of T-cells from which virus can be
recovered in test-tube experiments is consistent with
the assertion that the immune system is in overdrive
from the onset of infection by HIV' . But the new stud-
ies claim on average 105 units of 'free virus' (1) or
'plasma virion' per ml blood (2) in AIDS patients. That
should be enough virus to eliminate all remaining T-
cells of these patients, 105 per ml, within the two days
HIV needs to replicate (48) - unless, as Maddox sug-
gests, the 'new techniques for assaying the low levels
of virus involved were also necessary' (3) (amplifying

viral RNA with the polymerase chain reaction) possi-
bly because no infectious HIV could be detected by
conventional infectivity tests.
Indeed, Wei et al. acknowledge 'substantial propor-
tions of defective or otherwise non-infectious virus' .
'To determine whether the viral genomes represent-
ed in total viral nucleic acid correspond to infectious
virus .. .' they had to resort to the same techniques that
the 'old HIV hands', as Wain-Hobson calls them (43),
had used to isolate HIV from rare infected lympho-
cytes of AIDS patients: 'We cocultivated PBMCs ...
with normal donor lymphoblasts in order to establish
primary virus isolates'. Shaw together with some of
the investigators of Wei et al. had shown in 1993 how
to convert 'plasma viral RNA' to infectious virus. They
concluded that the 'quantitative competitive PCR' is
'as much as 60,000 times more sensitive' (49) than
infectious virus (16, 19). Divide 105 'plasma viral
RNA' units by 60,000 and you have 1.6 infectious
units per ml, a number that is consistent with numer-
ous previous reports (see above). Ho and a different
group of collaborators just published a paper in which
they show that over 10,000 'plasma virions', detect-
ed by the 'branched DNA signal-amplification assay'
used in their Nature paper, correspond to less than one
(!) infectious virus (50). Thus Wei et al. and Ho et al.
both reported titers of 105 biochemical virus-units that
really correspond to one or even less than one infec-
tious virus. However, infectivity is the only clinically
relevant criterion of a virus.
In other words, there is no evidence for infectious
virus in Wei et al. 's and Ho et al. 's patients. Wei et al.
and Ho et al. had apparently detected non-infectious
virus that had been neutralized by 'the immune system
[that] reacts hyperactively to HIV infection' - just as
Maddox suggests. Infectious virus was only obtained
by activating latent HIV from a few infected cells out
of millions of mostly uninfected cells from a given
AIDS patient. Such virus activation is only achieved
by growing cells in culture away from the hyperactive
immune system of the host,just as the 'old HIV hands'
used to do it, when they tried to isolate HIV from AIDS
patients (45, 46). Thus the paradox of too few viruses
to cause immunodeficiency remains unresolved.
In view of the evidence that there are no more than
1.6 infectious HIVs per ml blood in Wei's and Ho's
patients, one wonders whether the 105 viral RNAs per
ml are real or are an artifact reflecting inherent difficul-
ties in quantifyinr ~he input number of 'plasma viral
RNA' molecules after many rounds of amplification
by the peR. The problem with the quantification of
117
input RNAs - after 30 to 50 rounds of amplification
by the PCR (51) - is like calculating the number of the
original settlers in America, from the current number
of Americans and their current growth rates. But even
if the 105 'plasma viral RNAs' per ml were real, it is
hard to guess where they came from in view of 'the
scarcity of T-cells from which virus can be recovered
.. .' acknowledged by Maddox (3).
However, the apparent lack of infectivity of the
'free virus' or 'virions' (2) resolves the paradox of
the coexistence of 105 T-cells with 105 plasma viral
RNAs per ml blood in Ho et al. 's and Wei et al. 's
AIDS patients (1). Even HIV cannot kill T-cells that
it can not infect. The fact that over 99% of T-cells in
persons with AIDS are not infected by HIV (14, 26,
27, 31, 32,44), is definitive evidence that there is no
infectious HIV in typical AIDS patients. Clearly, in
AIDS patients with 1.6 infectious HIV units per ml
something other than HIV must cause AIDS.
In earlier efforts to resolve the paradox, that there
is too little HIV in AIDS patients to cause AIDS,
both groups have observed huge discrepancies between
virus titers and AIDS symptoms. In 1993, Shaw and
colleagues have described otherwise identical AIDS
patients of which 5 contained 0 infectious HIV per mI,
and 22 contained between 5 and 105 (16, 19). In 1989,
David Ho et al. have also described 40 AIDS patients
with virus titers ranging from less than 1 to 105 infec-
tious units per ml (30). In 1993, Ho et al. even report-
ed 12 AIDS patients, including 8 who had AIDS 'risk
factors', who were totally HIV-free: 'Specific antibody
assays, viral cultures, and polymerase chain reaction
(PCR) techniques' for HIV were all negative. Their
T-cell counts ranged from 3 to 308 per Jll (52).
There is only one consistent hypothesis to reconcile
the bewildering ranges ofHIV titers inHo's and Shaw's
patients with the role of the virus in AIDS - HIV
is a passenger virus, rather than the cause of AIDS.
Indeed, non-correlation between the titers of a virus
and disease, and between the very presence of a virus
and disease - is one of the hallmarks of a passenger
virus. Both Ho et al. and Shaw et al. have failed to
understand that rare correlations between a virus-at-
high-titer and a disease are the hallmark of a passenger
virus, and that consistent correlations between a virus-
at-high-titer and a disease are the hallmark of causative
virus (8, 53, 54). Therefore they have, contrary to their
claims, established HIV as a passenger virus of AIDS
patients.
(III) Why HN needs 10 years to cause AIDS. Until
HIV appeared on the scene, the latent period from
118
infection to disease was a function of the generation
time of a virus. A virus that replicates in 2 days and
produces 100 viruses per generation would cause dis-
ease in about two weeks - provided there is no antiviral
immunity. This is because 100 viruses infect 100 cells
producing 100 x 100 or 10,000 viruses 2 days later.
Within 14 days of such exponential growth 10 14 cells
- the equivalent of a human body - would be infected.
Therefore the latent periods of pathogenic retrovirus-
es, like Rous sarcoma virus, and non-retroviruses like
flu, measles, mumps, herpes, hepatitis, mononucleo-
sis, chicken pox are all 7 to 14 days (23). Since HIV
replicates in 2 days, like all other retroviruses (48),
and since according to Ho an infected cell produces
over 1000 viruses per 2 days (32), HIV should cause
AIDS, - if it could cause AIDS - just as fast as other
viruses.
Yet, as Maddox points out, the failure of HIV
to cause AIDS within weeks after infection presents
another paradox for the HIV-AIDS hypothesis, ' ... the
usually slow decline of CD4+ cells is not consistent
with what one would expect from a specific cytotox-
ic viral mechanism'. Indeed, both studies confirm the
paradox. Since the AIDS patients contain 105 'free
viruses/virions' and 105 T-cells per ml plasma, the
plasma of these patients should be T-cell free within 2
days, the generation time of HIV But Ho et ai. report
that the T-cells of AIDS patients are either steady or
even increasing over 1 month, and Wei et ai. report
that the T-cells of their patients remain either steady or
decline slowly over 5 to 8 months (1, 2).
Even if there are 50-times more T-cells in hidden
reservoirs - as Ho et al. report -, they, too, should be
infected within two weeks, because according to Wei
et aI., the 'plasma viral RNA' titer can rise two orders
of magnitude within two weeks. In fact, the ability of
HIV to increase from 10 3 'plasma viral RNA' units to
105 units per ml described by Wei et al. should only
be a fraction of the real 'dynamics of the infection
of people by HIV' (3), since it occurred despite the
presence of two DNA chain terminators, AZT and ddI,
used as anti-HIV drugs in addition to a new coded
antiviral drug.
Therefore it remains paradoxical that - dated from
the time of HIV infection - AIDS occurs at entirely
unpredictable times, currently estimated to average 10
years (5). To determine whether the currently unpre-
dictable time from HIV infection to AIDS can be rec-
onciled with a viral mechanism at all, one needs to
know whether HIV kills T-cells, how much infectious
virus there is, and the percentage of infected cells at a
given time. Since the new studies by Wei et ai. and Ho
et ai. provide none of these data, all new calculations
'on the dynamics of the infection of people by HIV
... in the process of understanding the disease called
AIDS' are worthless.
However, the hypothesis that HIV is a passenger
virus provides a consistent explanation for the unpre-
dictable time intervals between HIV infection and
AIDS. It is one hallmark of a passenger virus, that
the time of infection is unrelated to, and independent
of the time when a disease occurs - just as with HIV
and AIDS. Another hallmark of a passenger virus is
that its titer and even its presence are not correlated
with disease - just as was shown above for HIV and
AIDS.
The simplest interpretation of the slow decline of
T-cells in Ho's and Wei's AIDS patients is a non-viral
cause, e.g. long-term intoxication (7). Take for exam-
ple the slow decline of liver cells in long-term alco-
holics or of lung cells in long-term smokers.
Maddox seems concerned that 'reporting of the new
event has been curiously selective'. Perhaps even sci-
ence reporters begin to wonder how much further the
virus-AIDS hypothesis can be stretched to explain its
most obvious failures and inconsistencies: Why is there
no vaccine? Why does American/European AIDS stay
in the classical risk groups, male homosexuals, intra-
venous drug users and transfusion recipients? Why do
AZT-treated HIV-positivesget AIDS (55, 56)? Why do
918 HIV-positive male homosexuals who had 'avoid-
ed experimental medications on offer' and 'chose to
abstain or significantly reduce their use of recreational
drugs .. .' remain AIDS-free, long-term survivors (57)?
Why did the T-cells of29% of 1020 HIV-positive male
homosexuals and former intravenous drug users from
the placebo arm of a clinical AZT trial increase up
to 22% over two years - despite the presence of HIV
(58)? Why did the T-cells of 14 out of 31 HIV-positive
hemophiliacs treated with highly purified factor VIII
increase up to 25% over three years - despite the pres-
ence of HIV (59)? Why is there not a single study
showing that HIV-positive 20 to 50-year-old men or
women who are not drug users or recipients of trans-
fusions ever get AIDS (60)?
Why did neither Ho et al. nor Wei et al. identify
the risk groups their patients came from or indicate
whether they had Kaposi's sarcoma, dementia, or diar-
rhea or lymphoma? Can they exclude that recreational
drugs used by AIDS risk groups, like nitrite inhalants,
amphetamines, and cocaine are immunotoxic or car-
cinogenic (61)? Why is it that among 10 long-term (10
 119

to 15 years) survivors of HIV recently described by Ho 18. Clark, S.1., et a!. N. Eng!. J. Med. 324, 954-960 (1991).
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20. Mims, C. & White, D.O. Viral Pathogenesis and Immunology
Can Wei et al. and Ho et at. exclude that the DNA chain (Blackwell Science Publications, Oxford, 1984).
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23. Fenner, E, McAuslan, B.R., Mims, C.A., Sambrook, J. &
they aware that the manufacturer of AZT says in the White, D.O. The Biology of Animal Viruses (Academic Press,
Physician's l)esk Reference that "it was often diffi- Inc., New York, 1974).
cult to distinguish adverse events possibly associated 24. Gross, L. Oncogenic Viruses (Pergamon Press, Oxford, 1970).
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 120

nature " Little E•••• Slreet

london WC2H 3LF
Ttl: +44 (01171 836 6633
2 March 1995 fa.: +44 (0)171 836 9934
+44 (01171 240 6930
Peter H DUesberg
Department of Molecular
and Cell Biology
University of California
Berkeley, CA 94720

Dear Peter:
First, the good news: we shall publish the essence of what you
have to say. Sut there are obvious snags. Let me retail my
original conversation with Harvey Bialy. What format? he asked.
A letter, I said. That's too little, he said; what about 1,000
worod. I said I was not prepared to negotiate the length of a
letter not yet written. But what you have sent would take at
least 3 pages of Naeure.
second, I reeent the way in which you appear to have alerted the
world's press to the existence of your piece. Why do that?
Third, and this may not be such good news, I plan to go through
your piece with a fine-tooth comb with the'intention of ridding
it of repetitions and variou. misrepresentations.
Let mp. illustrate the la~t point by reference to your page 3 and
the continuation of the main paragraph on page 4. You .tart with
the phrase "HIV was proposed to follow an entirely unprecedented
course of action", you document various misconceptions about the
functioning of HIV and then you conclude with the phrase "this
HIV-hypothesis". Frankly, that smack. of the old Goebbels
tec~nique, that of creating a straw man from a farrago of
indefensible propositions and then knocking it down. I know of
nobody who, in the past decade, has put forward your points (1)
to (5) as a unified stat:ement of the conventional position. (Even
you have to assemble the position with 20 references.) On the
contrary. the "HIV .. hypothesis" is much simpler: "lilV causes AIDS,
in some manner not understood; most of those infected will
develop the disease".
Nor is it a fair representation of Wei et al. and Ho et al.
::'0 say that they "claim" to resolve the three specific
"pa:n... doxes" ~'ou list. In truth, they do nothing of the kind. The
only conceivable reference to the lo-year latency period. for
example. is in Ho et al .• and consists of the simile of the tap
A:'ld drain. To quote front Wei et al., "The kinetics of virus ...no.
C:J4' lymphocyte r.eplicat~on" imply "First, " . continuous rounds
0:: de novo virus infect:.on, replication and rapid cell t.urnOVI'll:"
probably represent a primary dri.lling force in HIV
p"~hogenesiEl ... Second ... a striking capacity or lhe v'i.:'VG :(;or
biolc;gically re:evant change. Third ... that virus production per'
se is directly invo:ved in CD4' cell destruction." He et a1. go

M.cltlfU,n Macazlnttl Ltd

Rtgl!lte'@c C'fi.:.:: ~t AbO'lit
Kf.f;j~r@rt'C ~~.Jr·~"'Rr. 93~S6~ Eng_jli,t)

John Maddox's letter of reply concerning Duesberg and Bialy's first version oftheir response.
 121

narnre
4 little Essex street
London WC2R 3LF
Tel: .44(0)171 8366633
Peter H Duesberg Fax: +44 (01171 836 9934
+44 (0)171 240 6930
2 March 1995
l'age 2

further, but only to this extent: Our findings strongly

support the view that AIDS is primarily a consequence of
continuous high-level replication of HIV-l, leading to virus and
immune-mediated killing of CD4 lymphocytes."
My position as an editor is that straight misrepresentations such
ilS these haVE: no place in a journal like this. You complain at
an earlier seage that I nave improperly "personalized" this
argument. How do you suppose that Wei et a1. and Ho et al. would
feel if we were to publish your travesty of what they have said?
My Buggestion, therefore, is that you throwaway the first four
pages of your introduction, and devise a less inflammatory
introduction in which you state that t.he two papers have not
changed your view, and go on to giVe the reasons. Please let me
know whether that is acceptable. I have some other less radical
comments on the remainder of the text, but there's no point in
sending them at this stage if you cannot agree to something along
the lines I have suggested.
Yours sincerely,

I
John Maddox
Editor

CO! Harvey Bialy

Rt".e::!.lerttl Oi'iGl1. <IS above

~ei>ste:ecJ "JJ"~lt': 93g.~65 (l1iiiW()
122
March 7,1995
Sir John Maddox
Nature, Macmillan Publishing
4 Little Essex St., London, WC2R 3LF
England
Dear John,
After you have invited us with an editorial "to com-
ment" on "the new view of HIV" (Nature, 19 January
1995), we are surprised to learn that you only want to
"publish the essence of what [we] have to say".
We have followed your advice that "it should be no
longer than it needs to be". Since neither of the two
new Nature studies nor the two accompanying News
and Views by you and Wain-Hobson have explained
the old view of HI V, we had to explain the old view first
for the reader of Nature to understand our comments on
"the new view of HIV". We are not interested in a dis-
cussion between experts restricted just to titers of HIY.
Therefore we can not accept your suggestion to "throw
away the first four pages" of our commentary.
Moreover, if our commentary comes out to be 3
pages in Nature, as you say, that would only be a
fourth of the space you have already dedicated to the
"new view of HIV" - 10 pages for the two papers and 2
pages for the two editorials. A 3-page commentary on
12 pages in Nature, supplemented by an international
press release, is hardly a convincing argument that "it
is longer than it needs to be".
You write that you "resent the way in which [we]
appear to have alerted the world press to the existence
of [our] piece". However, we are afraid, if alerting
the world's press is a reason for resentment, we should
resent you. After all, you have alerted the world's press
using the power of your office about the "embarrass-
ment for Duesberg" and that you "eagerly awaited"
our "comment". But you did not respond to our com-
mentary from February 7 until March 2. As a result
of your activities the world's press has called us, and
some callers were given our commentary, weeks after
you had received it, with the proviso that it may not
be published in its present form by Nature. Indeed, the
exchange of opinions is protected by the free-speech
amendment in this country.
Are you aware that both Wei et at. and Ho et al.
gave their papers to John Coffin and David Baltimore
prior to publication in Nature to write editorials for
Science (267, 483, 1995) and NEJM (332, 259-260,
1995) respectively?
If you plan to meet your published commitment
that "his [Duesbergs] and his associates' views on the
new developments should be made public" by first
cutting, and then editing our commentary with a "fine-
tooth comb with the intention of ridding it of... various
misrepresentations", we do not see a basis for an open
debate with you.
In response to your letter we resubmit our
manuscript with some revisions:
1) page 2, third paragraph:
Replace "despite these 'new studies'" by "in light of
these new studies".
2) page 2, fourth paragraph:
Insert after "immunodeficiency syndrome (AIDS)", "if
antibody to HIV is present".
3) page 3, item (2):
According to Shaw, Ho and their collaborators, HIV
activity is "rapidly and effectively limited" by this
antiviral activity17,18.
4) page 4, second paragraph:
Replace the sentence "The new studies claim to
resolve ... " by "The new studies are claimed by two
News and Views articles from Maddox (3) and Wain-
Hobson (43) to resolve the paradoxa, (I) how HIV kills
T-cells, (II) how HIV causes AIDS, and (III) why HIV
needs 10 years to cause AIDS."
5) page 6, end:
Insert the following paragraph after " ... numerous pre-
vious reports (see above)":
"Ho and a different group of collaborators just pub-
lished a paper in which they show that over 10,000
"plasma virions", detected by the "branched DNA
signal-amplification assay" used in the Nature paper
correspond to less than one 0) infectious virus 50 . Thus
Wei et al. and Ho et at. both reported titers of 105 bio-
chemical virus-units that really correspond to one or
even less than one infectious virus. However, infectiv-
ity is the only clinically relevant criterion of a virus."
6) page 11:
Insert after "are immunotoxic or carcinogenic?", "Why
is it that among 10 long-term (10 to 15 years) survivors
of HIV recently described by Ho et al. 50 'none had
recei ved antiretroviral therapy ... '?"
References:
17. Daar, B.S., MoudgiJ, T., Meyer, R.D. & Ro, D.O. N. Engl. 1.
Med. 324,961-964 (l99\).
18. Clark, SJ., etal. N. Engl. 1. Med. 324, 954-960 (1991).
50. Cao, Y., Quin, L., Zhang, L., Safrit, J. & Ro, D.O. N. Engl. 1.
Med. 332,201-208 (1995)."
Sincerely,
Peter Duesberg, Harvey Bialy (faxed)
CC: Confirmation copy

On May 18, 1995, Nature publishes a Duesberg-Bialy letter flanked by two editorial comments
AIDS pathology unknown: HIV infection
provokes hyperactivity of the immune system,
but the causes of that are far from understood
'The second arresting feature of this correspondence
is the letter from Dr. Peter Duesberg and his col-
league, Dr. Harvey Bialy, which has been published
without change. Sadly, there seems no way in which
the authors concerned can be persuaded that 'free and
fair scientific debate' is ordinarily understood to mean
a progressive process, one in which each of two sides
learns from what the other says. A restatement of ear-
lier and well-known positions is not that at all. On this
occasion, Duesberg and Bialy's citation of Loveday in
their cause is especially inappropriate given Loveday's
name among the authors of a letter supporting Wei et
al. and Ho et al. But no further solicitation of Dues-
berg's opinion is called for'.
[Nature 375, p. 167 (1995)]
HIV an illusion
SIR - In an editorial (1) in the 19 January issue of
Nature, John Maddox invited 'Duesberg and his asso-
ciates' to comment on the 'HIV-l dynamics' papers
published the previous week, indicating that these new
results should prove an embarrassment to us. Although
we do not think that a scientist should be embarrassed
for pointing out that inconsistencies and paradoxes in
a hypothesis that have only been reportedly resolved
10 years later, we nonetheless prepared a fully refer-
enced, approximately 2,000-word critique or the Ho et
al. (2) and Wei et al. (3) papers that we believed met
the criteria of 'not being longer than it needs to be, and
pertaining to the papers at hand' that Maddox set out
in his widely read challenge.
Unfortunately, he did not share our view and agreed
to publish only a radically shortened version, and only
after he had personally 'gone over it with a fine-tooth
comb' to remove our perceived misrepresentations of
the issues. We found these new conditions so totally at
variance with the spirit of free and fair scientific debate
that we could not agree to them.
Readers of Nature who are interested in these ques-
tions, and feel that they do not need to be protected
by Maddox from our ill-conceived logic, can find the
complete text of our commentary in the monograph
123
supplement to the most recent issue of Genetica (4).
Here we would point out only that the central claim of
the Ho et al. (2) and Wei et al. (3) papers - that 105
HIV virions per ml plasma can be detected in AIDS
patients with various nucleic-acid amplification assays
- is misleading. The senior author of the Wei et al.
paper has previously claimed that the PCR method
they used overestimates by at least 60,000 times the
real titre of infectious HIV (5): 100,000/60,000 is 1.7
infectious HIVs per ml, hardly the 'virological may-
hem' alluded to by Wain-Hobson (6). Further, Ho and
a different group of collaborators have just shown (7)
that more than 10,000 'plasma virions', detected by
the branched-DNA amplification assay used in their
Nature paper, correspond to less than one (!) infectious
virus per ml. And infectious units, after all, are the only
clinically relevant criteria for a viral pathogen.
Finally, in view of Wain-Hobson's statement (6)
that 'the concordance of their [Wei and Ho's] data is
remarkable', note that Loveday et al. (8) report the
use of a PCR-based assay and find only 200 HIV 'viri-
on RNAs' per ml of serum of AIDS patients - 1,000
times less than Ho and Wei. So much for the 'remark-
able concordance'.
Peter Duesberg
Department of Molecular and Cellular Biology,
University of California,
Berkeley, California 94720, USA
Harvey Bialy
Bio/Technology, New York,
New York 10010, USA
References
1. Maddox, J. Nature 373.189 (1995).
2. Ho. D. D .• et al. Nature 373. 123-126 (1995).
3. Wei. X .• etal. Nature 373.117-122 (1995).
4. Duesberg. P. & Bialy. H. in AIDS: Virus- or Drug-Induced? (ed.
Duesberg. P.) (Kluwer. Dordrecht. 1996).
5. Piatak. M .• et al. Science 259. 1749-1754 (1993).
6. Wain-Hobson, S. Nature 373, (1995).
7. Cao, Y., Quin, L., Zhang, L., Safrit, J. & Ho, D. D. N. Eng!. J.
Med. 332, 201-208 (1995).
8. Loveday, C .• et al. Lancet 345,820-824 (1995).
124

• Peter Duesberg was offered space in Scientific

Correspondence for 500 words of his own choice,
but declined. - Editor, Scientific Correspondence.
[Nature 375, p. 197 (1995)J

TO: Sir John Maddox

Editor, nature
Porters South, Crinnan St.
London, England
FROM: Peter Duesberg
Date: July 10/95

Dear John,

Following publication of the Duesberg-Bialy letter on May 18, Nature added:

"Peter Duesberg was offered space in Scientific Correspondence for 500 words of
his own choice but declined."

Since our letter used up that "space", Nature's comment is erroneous and should
be retracted.

Could you please confirm or un-confirm our conclusion. I have faxed to you
twice before requesting an answer to this question Oune 20 and June 22, 1995) but
have not received a reply.

Sincerely, Peter Duesberg

cc Harvey Bialy
 125

nature
Porters South
4-6 Crinan Street
London f>.!l 9SQ

In reply please quote: Tel: +44 (0)171 833 4000

Fax: +44 (0)171 843 4596/7
DUESBERG MC/eg

19 July 1995

Dr P Duesberg
Dept Molecular & Cell Bio, c/o
stanley/Donner Admin Services ut
University of California
229 Stanley Hall
Berkeley CA 94720

Dear Dr Duesberg,
Thank you for your various faxes. We offered to publish a 500-
word version of your response to Ho/Shaw in our issue in which
we published other comments on those papers. You declined, and
instead send us a complaint that we would not publish your long
manuscript. We published that complaint. As far as we are
concerned, the matter rests.
Yours sincerely,

Dr Maxine Clarke
Executive Editor
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 127-130, 1996.
© 1996 Kluwer Academic Publishers.
HIV: Science by press conference
Mark Craddock
School of Mathematics and Statistics, University of Sydney, Australia
One of the most disturbing aspects of what passes for
AIDS research these days, is the separation between
what researchers actually find, what they tell the press
conference and what the media tells the public. To
assume that these three are identical or even simi-
lar would be pure folly. The press conference has a
venerable history in AIDS science. When Robert Gal-
lo's group 'found' that 26 out of 72 AIDS patients
had small amounts of newly discovered retrovirus in
their bodies, this interesting but unconvincing work
was transformed by the magic of an officially sanc-
tioned press conference into the announcement of the
'probable cause of AIDS' . And Gallo's modest findings
became 'compelling evidence' that this new retrovirus
was the cause of AIDS. Ten years later nothing has
changed.
In 1993 another press conference announced that
large amounts of HIV had been found in lymph glands
in HIV positive people. The HIV skeptic's claims that
HIV cannot cause AIDS because it is present in only
minute quantities was finally laid to rest. The lymph
glands were 'packed' with HIV in HIV positive people.
It is just a pity that the facts did not match the hype.
The press conference where the findings on HIV in
lymphoid tissue were announced, was given by Dr.
Anthony Fauci and Dr. Ashley Haase, and the results
appeared in Nature on March 25 1993 in back to back
papers. Oddly enough if you read these papers, the
results do not actually seem to be what was claimed
at the press conference. In the paper by Fauci's group
(Pantaleo et al., ibid) it is stated that 12 patients were
studied and results for 3 of them are hidden away in
the caption to figure 1. They actually found HIV in
only 1 in 1000 T cells in 2 of the three, and between
1 in 10 and 1 in 100 in the third, a patient with full
blown AIDS. In other words they found no more HIV
than anybody else ever has. How then do we explain
the extravagant claims at the press conference? It is
probably safer not to try.
127
Skip forward 2 years and we are back at another
press conference. This time it is January 12, 1995 and
David Ho and George Shaw are presenting the results
of a study which seems to turn the last 10 years of
HIV research on its head. Using new drugs and new
techniques Ho and Shaw have found that HIV is an
incredibly active virus, producing billions of offspring
every 2 days, and killing billions of T4 cells in a battle
to the death with the immune system. Once more the
HIV sceptics have been and the answered. The jour-
nalists, lead by Lawrence K. Altman ofthe New York
Times rush to tell us that a massive battle is going
on between the virus and the immune system from
the beginning of infection, a battle that lasts 10 years
and that the immune system can only win if we pump
healthy HIV positive people full of experimental drugs
with no demonstrated benefits.
But stop for a minute. It is all too easy to be swept
away by the hyperbole of journalists and the enthusi-
asm of scientists for their own work. (I say this as a
scientist, but the easiest way to engage a scientist in
conversation is to ask about their work. And scien-
tists are extremely bad at judging the quality of their
own work). We have to ask fundamental questions
here. Does what Ho and Shaw say actually make any
sense? Are their experimental techniques sound? Do
their conclusions follow from their results? Is their
mathematical analysis sound? If we are to evaluate
the worth of this work we have to answer these ques-
tions. In fact we have to answer these questions for just
about any scientific paper ever written, so we should
certainly not spare HIV researchers. Particularly as we
can be certain they will not ask themselves these ques-
tions. These are the issues that I will address now. My
conclusion will be that this new work is about as con-
vincing as a giraffe trying to sneak into a polar bears
only picnic by wearing sunglasses (as Ben Elton might
say).
128
To begin with, what were these people trying to
do? They wanted to measure the rate at which both
HIV and T cells are produced in infected people. The
idea is deceptively simple. You measure the viral load
in a patient at a given time, then you pump them full
of 'antiviral' drugs. The drugs reduce the amount of
virus present in the blood by some factor. (Claimed
to be an implausible 98.5% in these papers. Implau-
sible because there is no possible way that viral load
can be measured as accurately as the figure of 98.5%
suggests). You then wait till HIV magically mutates
into 'drug resistant' strains, and wait till the viral load
returns to pre treatment levels. This gives an estimate,
through some relatively simple mathematics, for the
rate at which the virus replicates. Both Ho and Shaw's
groups found that in the absence of viral clearance, the
total amount of virus in the body should double every
2 days. So suddenly the low levels of viral replication
found over the past decade are thrown out the window,
and HIV is now the cause of a relentless battle, a battle
that takes place over a decade or more. The measure-
ment of T cell production can be made in much the
same way.
So our question must be whether or not we should
believe these results? After all at the last big press
conference, Ashley Haase's group (Embretson et al.,
Nature, March 25, 1993) found low levels of HIV RNA
in the T cells of patients studied (4 people, one of whom
had no HIV proviral DNA at all) indicating 'low levels'
of viral replication. So what do we do when one press
conference seems to contradict the other? Clearly we
have to examine both studies carefully.
As a mathematician, I was intrigued by the claim
of John Maddox, editor of Nature, that the new results
provide a new mathematical understanding of the
immune system. Unfortunately, my confidence in this
claim was badly shaken when it turned out that on the
very first page of the Shaw paper (Wei et al., p 117,
Nature, Jan 12, 1995) they make an appalling math-
ematical error. And in the same paragraph make an
assumption which turns out, by their own admission to
have no basis in observation, and which they give no
justification for. The authors of Wei et at. are attempt-
ing to give a mathematical formula for the amount v
of free virus at time t. They state that virus is pro-
duced by virus producing cells y, at rate k, and decays
exponentially at rate u. These two statements are mutu-
ally contradictory but that is not a real problem. If they
change the word 'decays' to 'is cleared' then all is well.
This leads to what is known as a differential equation
for v which may be solved easily. (Craddock, letter to
Nature unpublished». They state a formula for v based
on their assumptions, which unfortunately is complete-
ly wrong. Confidence that anything good will come out
of this paper plummets at this point. Their result for v
is not only wrong, but it does not even look right. You
do not have to be a mathematician to realise that if the
rate at which v is produced depends on ky(t), where
yet) is the number of virus producing cells at time t,
then v is going to depend upon ky(O), where yeO) is the
initial size of the virus producing cell population. So
one wonders how they manage to produce a formula
for v which does not depend upon ky(O) at all?
And they state in the same paragraph that virus pro-
ducing cells can to 'a good approximation' be assumed
to decline exponentially. They then state a few lines
further down that they 'have data only for the decline
of free virus, and not for virus producing cells'. If
they have no data for virus producing cells then how
can they possibly know that these cells decline expo-
nentially? They might do anything. That is the whole
point of not having any data. You do not know what is
happening.
The problems that these errors entail are self evi-
dent. They are trying to estimate viral production rates
by measuring viral loads at different times and trying
to fit the numbers to their formula for free virus. But
if their formula is wrong, then their estimates for viral
production will be wrong too.
As bad as these mistakes are, they are only the
beginning. It turns out that the whole basis for the mea-
surements given in both papers is an unvalidated tech-
nique. Namely Quantitative Competitive Polymerase
Chain Reaction. QC-PRC is based upon a deceptively
simple idea. PCR mass produces fragments of DNA.
You start with a small amount of DNA and after each
PCR cycle the amount of DNA you have is between 1
and 2 times the amount at the beginning of the cycle.
Thus the amount of DNA you have to study increases
exponentially. The fact that the PCR is an exponential
growth process means that experimental errors will
also grow exponentially, so that you need to be very
careful about what you do with the process. A number
of people have decided that is should be possible to
estimate the amount of DNA present in a sample by
using PCR. This is so called quantitative competitive
PCR. The idea is to add to the sample to be estimated
a known amount of similar but distinguishable DNA
and amplify both together. The assumption is that the
relative amounts of the two products should stay the
same, and hence you can work out the size of the sam-
ple you started with by knowing the ratio of the two,

determined by observation when PCR has produced
enough of both to measure, and how much control
DNA was added. What is absolutely crucial is that the
relative sizes of the test DNA and your known con-
trol must remain EXACTLY equal. Close is not good
enough. Because the slightest variations will be mag-
nified exponentially and can produce massive errors
in your estimate. The difficulties in using PCR quanti-
tatively were pointed out by Luc Raemaeykers in the
journal Analytical Biochemistry in 1993. He demon-
strated that published papers on QC-PCR contain data
that show the fundamental assumption that the rela-
tive sizes of the samples remains constant is not met
in practice. Despite this HIV researchers continue to
use PCR to quantify viral load. The bottom line in all
of this is that data obtained using QC-PCR must be
treated with extreme caution. There is simply no way
of knowing whether a given estimate is correct or is
100 000 times too high!
So we have an extraordinary problem already. We
do not know whether or not the data that Shaw and Ho's
groups obtained is actually meaningful. And the math-
ematical basis of the analysis used by Shaw's group is
to say the least questionable. But these groups actual-
ly manage to do a lot worse than this. Neither group
compared the rate of T4 cells generated in the HIV
positive patients with HIV negative controls! Both
groups assert that in HIV infected individuals, up to
5% of the circulating T4 cells are replaced every 2
days. This information is hardly new, Peter Duesberg
says something similar in a paper in the proceedings of
the National Academy of Sciences from 1989. Except
he states that 5% of the bodies T cells will be replaced
every 2 days, in healthy people.
The logic here is remarkable. It is claimed that HIV
sends the immune system into overdrive as measured
by a supposedly accelerated production of T4 cells.
Between 100 million and 2 billion are produced each
day in the patients that were studied. But where are the
healthy controls? How can this production of T cells
be ascribed to HIV if there is no comparison made with
healthy people? And even if there were a comparison,
how can the production by unambiguously attributed to
the 'battle' with HIV? The patients in both study groups
were being treated with new drugs such as Nevarap-
ine (we are naturally told nothing of possible toxic
side effects of these drugs) whose effects are largely
unknown. So how can these results be extrapolated to
HIV positive people who are not taking these drugs? It
must surely be admitted that the system they are trying
to study, namely the interaction of HIV with T4 cells,
129
might behave substantially differently in people who
are not being pumped full of new drugs, in addition to
'antiretrovirals' like Zidovudine?
Yet HIV 'science' has declined so far that these ele-
mentary questions are addressed neither by the research
groups themselves, nor the referees at Nature whose
job it is to critique the papers before publication. Is
nobody at Nature bothered by the fact that neither paper
contain any hard data which can be independently anal-
ysed? And Wei et al., use a technique for measuring
viral load known as branched DNA. (bDNA). yet their
data for bDNA does not appear in the paper. The reader
is given absolutely no explanation of how this assay of
viral load is supposed to be carried out, and no indi-
cation of how reliable it is. All questions on bDNA
are referred to 3 papers in preparation. But nobody
in the HIV research community is at all bothered by
this. They seem to have learned like the mad hatter
to believe 6 impossible things before breakfast and so
one more makes no difference. One gets a remarkable
sense of being disassociated from the real world when
entering the realm of AIDS research. Am I mad or are
they?
We are to believe from Wei et al., that variation at a
single place in the HIV genome can confer immunity to
the virus against the new drugs. (In which case what is
the point of administering them?). Yet currently PCR
uses the DNA polymerase (the enzyme in cells that
makes new DNA from old) from Thermus Aquaticus.
This 'Taq' polymerase has not proof reading capacity.
We then have to ask: are changes in the genome of HIV
that appear after drug therapy due to the virus mutating,
or are they an artifact of the PCR technique's inability
to correct errors? There are no prizes for guessing how
much attention the authors of both studies pay to this
question. None.
Other people have made powerful objections to
these papers based upon biochemical considerations.
Duesberg and Bialy have written a superb critique,
as have Eleni Eleopulos-Papadopulos, Val Turner and
John Papadimitrou (although astonishingly their letter
to Nature was rejected. What a shock!) As I have made
clear, there are many problems that I see with these
studies, but us as a mathematician, I have left what I
consider to be the worst till last. The problem is this.
If there is so much HIV present, and it is replicating so
fast, why does 'HIV disease' take ten years to progress
to AIDS?
In Ho et al., they use the analogy of a sink with
the drain open, and the water pouring in from a tap at
a slightly lower rate that it drains away. So you get a
130
slow steady decline in CD4 cells. Ho et al. have a few
equations that are supposed to describe the changes in
virus levels and CD4 cells over time. What do these
equations actually predict, as opposed to what Ho et al.
say they predict? In order to make them work you have
correctly formulate them, which Ho et al. do not. When
correctly formulated (Craddock, Ibid) what emerges is
stunning. Ho et al.'s observations combined with their
simple model for T cells and virus, predict that the
T cell count should reach an equilibrium state quick-
ly. Meaning exponentially fast. It is actually difficult to
understand exactly what the equation on p 126 of Ho et
al. is supposed to mean, but it definitely predicts that
equilibrium is approached exponentially. When you
add terms to the equation to describe the effects of Virus
(inexplicably, they do not include the effects of the
virus on the T cell population in their model. I thought
HIV was supposed to be killing these cells somehow),
then include the expression for the amount of virus
that they give on p 124, you get a picture of 'HIV dis-
ease' that bears no relation to what happens in actual
patients. AIDS should develop in days or weeks. There
is no possible way it can take ten years. This emerges
from Ho et aI's., own model. They seem blissfully
unaware of the prediction that their own results give.
They probably have not bothered to look at tedious
questions like' do our results correspond with what we
observe in patients?'
Science is about making observations and trying to
fit them into a theoretical framework. Having the theo-
retical framework allows us to make predictions about
phenomena that we can then test. HIV 'science' long
ago set off on a different path. It seems as if nobody
bothers to check the details in this field. Nobody is ask-
ing the fundamental questions, and nobody wants to.
People who ask simple, straightforward questions are
labelled as loonies who are dangerous to public health.
Yet we desperately need people to ask the questions.
And it does not matter what the answers to the ques-
tions are as long as they are asked. My question is this?
Just what exactly will it take to get the people doing
HIV research to turn away from high tech, unproven
methods, arcane speculations about molecular interac-
tions etcetera etcetera and ask themselves 'Do any of
us have the faintest idea what we are doing?'
P. H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 131-141, 1996. 131
© 1996 Kluwer Academic Publishers.

AZT toxicity and AIDS prophylaxis: is AZT beneficial for HIV+

asymptomatic persons with 500 or more T4 cells per cubic millimeter?

Malcolm D. Zaretsky
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
Address for correspondence: Dept. of Molecular and Cell Biology, Life Sciences Addition, University of
California, Berkeley, CA 94720, USA

Received 10 May 1994 Accepted 28 July 1994

Key words: AIDS, AZT, CD4 T-Cells, prophylaxis, toxicity

Abstract
Analyses of the effects of prophylactic use of zidovudine (AZT) on progression to acquired immune deficiency
syndrome (AIDS) in human immunodeficiency virus seropositive (HIV +) asymptomatic persons with T 4lympho-
cyte (CD4+) cell counts 2: 500/mm3 is reported for data obtained from two studies, the Australian European Group
Collaborative Study, a multi-centered double-blind placebo-controlled clinical trial of the effects of AZT on pro-
gression to AIDS and other clinical endpoints, and the San Francisco Men's Health Study, an observational cohort.
The analyses of the data of both studies demonstrate no benefit from AZT treatment in terms of progression to
AIDS for those who are asymptomatic with CD4+ cell counts 2: 500/mm3 • The analysis of the San Francisco study,
performed with Kaplan-Meier survivorship estimates, indicates a heterogeneity in the efficacy of AZT between
baseline CD4+ cell count strata, 200-499/mm3 and 500-800/mm3 • Within the 200-499 stratum, 47% of those
receiving AZT therapy and 62% of those not receiving AZT therapy progressed to AIDS during the study period.
By contrast, within the 500-800 stratum 41 % of those receiving AZT therapy and 27% of those not receiving AZT
therapy progressed to AIDS during the same period. Application of the Cox proportional hazards survivorship
regression model for the relative risk of progression to AIDS to these same data accounts for this heterogeneity.
The model includes an interaction between AZT treatment and baseline CD4+ cell counts. The hematological
toxicity of AZT, demonstrated in clinical studies and laboratory investigations, indicates a biological correlate for
this interaction: the toxic effects of AZT on the more intact immune system of those with CD4+ cell counts in the
500-800/mm 3 range.

Abbreviations: ACTG - AIDS Clinical Trials Group; AIDS - Acquired immune deficiency syndrome; AMT
- 3'-arnino-3'-deoxythymidine; ARC - AIDS-related-complex; AZT - 3' -azido-3'-deoxythymidine, zidovudine;
BPU-E - Erythrocyte burst-forming units; CD4+ - T4lymphocyte; CPU-GM - Granulocyte macrophage colony-
forming units; EAGCS = European-Australian Group Collaborative Study; HIV = Human immunodeficiency virus;
SFMHS = San Francisco Men's Health Study.

Introduction source of serious reservation regarding their applica-

Efficacy ofAZT
From the outset of the discovery that they are
inhibitors of reproduction of human immunodeficien-
cy virus (HIV) in culture (Mitsuya et al., 1987;
Yarchoan & Broder, 1987), the toxicity of 3'-
azido-3'-deoxythymidine (AZT, zidovudine) and oth-
er deoxynuc1eosides of similar structure has been a
tion as anti-AIDS therapy.! These substances were
1 'The severe toxicity of AZT to bone marrow, as well as unex-
pected interactions of other drugs with AZT, indicate the importance
of knowing more about the effect of the compound .... It is remark-
able that so little basic information has been made available on toxic
compounds expected to cost hundreds of millions of dollars in a pan-
ic determined stopgap effort to reduce the lethal effects of AIDS'
(Seymour S. Cohen, 1987).
132
originally designed to be DNA synthesis chain ter-
minators for cancer chemotherapy. Toxic effects of
AZT were reported in the initial clinical trial of AZT
for efficacy and toxicity with 282 patients given 8-24
weeks of treatment with AZT, 1500 mg/day or a place-
bo; this trial resulted in its licensing for therapeutic use
on symptomatic patients with AIDS or AIDS-Related-
Complex (ARC) (Fischl et at., 1987; Richman et at.,
1987).
The basis for approval of the use of AZT in asymp-
tomatic patients with 200-500 CD4+ cells/mm3 was
provided by the AIDS Clinical Trials Group (ACTG)
study 019 with 1338 asymptomatic mv seropositive
patients having fewer than 500 CD4+ cells/mm3, giv-
en doses of AZT at either 1500 mg/day or 500 mg/day
or a placebo, of one year duration, and followed for
up to 2 years. This study concluded that AZT, at both
doses, was effective therapy compared with placebo in
delaying the onset of AIDS in this group (Volberding
et at., 1990). Anemia, neutropenia and nausea were
significant toxicities at the higher AZT dose. Nausea
was the only significant toxic effect at the lower AZT
dose. However, a recent re-examination of the data of
this study by a new group of investigators, including
the first author of the original paper, concluded that the
harmful effects of AZT on quality of life, concomi-
tants of its toxicity, resulted in no net benefit to these
asymptomatic mv+ patients (Lenderking et at., 1994).
Follow-up for four years of these patients in the 300-
500 CD4+ cells/mm3 range showed a benefit in terms
of an unspecified delay in progression to AIDS, but no
benefit in terms of overall survival rate (unpublished
data of ACTG 019, cited in Sande et at., 1993).
The question of when AZT therapy should be ini-
tiated, or, indeed, whether AZT should be used at
all, given its established toxicity, remains unresolved.
The guidelines for AZT therapy of the U.S. Nation-
al Institutes of Health (NIH) indicate AZT as first-
line therapy for all who are symptomatic, i.e. with
AIDS or severe ARC, regardless of CD4+ (T4) cell
counts and for those with CD4+ cell counts that are
less than 5OO/mm 3, with or without symptoms. For
those who are mv+, asymptomatic, with CD4+ cell
counts ~ 5OO/mm3, and who have had no prior anti-
retroviral treatment, the NIH guidelines recommend
that AZT or other anti-retroviral therapy not be initi-
ated but does indicate that such therapy be considered
if CD4+ counts should decline rapidly or if there are
laboratory changes that indicate disease progression
(Sande et at., 1993). The rationale for these guide-
lines are provided by the results of the Concorde trial
(Aboulker & Swart, 1993; Seligmann et at., 1994),
a large placebo-controlled trial with 1748 participants
and a median follow-up of 3.3 years. This trial found
an advantage to being in the immediate group after 1
year, in terms of progression to AIDS, which was lost
by 18 months. Moreover, this trial demonstrated that
AZT therapy did not provide additional benefits with
regard to progression to AIDS, ARC or death for those
who initiated it when they were asymptomatic but HIV
seropositive (immediate group), rather than delaying
AZT therapy until they developed disease symptoms
(deferred group).
By contrast, another recent placebo-controlled
clinical trial, the multi-centered European-Australian
Group Collaborative Study (EAGCS), with 3 years of
follow-up, concluded that AZT benefits asymptomatic
persons with CD4+ cell counts ~ 500/mm3 at baseline,
as well as those with lower CD4+ cell counts (Cooper et
at., 1993), and this view has received support (Bartlett,
1993). This interpretation of the EAGCS results is
questionable. The NIH guidelines cite the EAGCS, in
addition to the Concorde trial, for its rationale to rec-
ommend that AZT not be used by mv+, asymptomatic
patients with CD4+ cell counts 500-800/mm3 (Sande
etat.,1993).
My analysis of data from the San Francisco Men's
Health Study (SFMHS) (Lang etat., 1987; Winkel stein
et at., 1987) will demonstrate that AZT is not beneficial
to those with CD4+ counts of 500-800/mm3. Likewise,
my analysis of the published data of the EAGCS is pre-
sented in this paper; their conclusion that AZT is ben-
eficial to this group should be re-examined. Thus, the
analyses that are presented in this paper for those who
are HIV seropositive and asymptomatic with CD4+
counts of 500-800/mm 3 from both an observational
cohort and a clinical trial group suggest that the toxic
effects of AZT outweighs its benefits as an anti-viral
agent that delays progression to AIDS.
Toxicity ofAZT
A number of clinical, laboratory and in vitro studies
have provided extensive evidence for AZT toxicity
and its mechanisms at clinical concentrations. Hema-
tological toxicity of AZT has been demonstrated in
several clinical trials. The action of AZT at the cel-
lular level underlies the toxicity observed when it is
applied therapeutically in clinical trials and in obser-
vational cohorts. The AZT Collaborative Working
Group Trial, a multi-centered double-blind placebo-
controlled trial with 288 participants, demonstrated
significantly greater frequencies of hematologic toxici-

ty among those receiving AZT compared with placebo,
as measured by hemoglobin level, white cell count and
neutrophil count (Richman et al., 1987). A continua-
tion of this trial as an open label one with 229 patients
indicated anemia and granulocytopenia to be the prin-
cipal toxicities resulting from AZT therapy (Richman
& Andrews, 1988). A 3-5 fold increase in initial occur-
rence of granulocytopenia was observed in the sec-
ond year of AZT therapy compared with that of the
first year, indicating that toxicity from AZT therapy
is cumulative, there being a process at the cellular
level which reaches clinical threshold with durations
that vary with individuals, depending on other factors.
Hematological toxicity, 4-fold greater in the immediate
than in the deferred group, was reported to be the most
frequent reason for reduction of AZT dose in the Con-
corde trial. The estimated proportions with anemia,
hemoglobin counts :5 10 gldL, increased with duration
of AZT therapy: 5.3% and 0.9% in the immediate and
deferred groups, respectively, 1 year after the start of
the trial, increasing to 8.5% and 2.1 % at 3 years, pro- .
vides additional clinical evidence that the toxic effects
of AZT are cumulative (Seligmann et al., 1994).
Laboratory results provide additional evidence that
indicates AZT is toxic to the immune system. In the
multicenter Canadian AZT trial morphological obser-
vations during 36 weeks of AZT treatment were per-
formed on bone marrow cells from 65 HIV+ patients
who were not diagnosed as having AIDS (Centers for
Disease Control, 1987) and whose bone marrow cell
morphologies were normal at baseline. Morphologi-
cally abnormal bone marrow cells appeared in 62 of
the 65 subjects after 18 weeks of treatment with AZT
and persisted for the full duration of AZT treatment, 36
weeks (Gelmon et aI., 1989). Studies of the dynamics
of the suppression of granulocyte count from AZT ther-
apy indicate a linear relationship between the decrease
in granulocyte count from baseline and the duration of
AZT exposure over a period of 12 weeks (Drusano,
1993). The steady state plasma concentration of AZT
required to produce decline, 3 JIM, is within the range
of AZT plasma concentrations measured in patients
undergoing AZT therapy (Gitterman et aI., 1990).
The toxic effects of AZT on human hematopoietic
bone marrow cells have been demonstrated in vitro.
The effect of AZT on the survival fraction of progeni-
tor cells is dose-dependent in both the case of granulo-
cyte macrophage colony-forming units (CFU -GM) and
erythrocyte burst-forming units (BFU-E). The mean
concentrations of AZT required for 50% inhibition of
CFU-GM and BFU-E cells were found to be 2.4 JLM
133
or less (Sommadossi & Carlisle, 1987; Johnson et aI.,
1988; Ganser et aI., 1989) and similarly with murine
bone marrow cell cultures (Luster et al., 1989). Plas-
ma concentrations that are normally reached in clinical
doses of AZT, 1-2 JLM, might well, therefore, have a
suppressive effect on bone marrow precursor cells, a
consequence of the blocking of cellular nucleic acid
synthesis by AZT, through its incorporation into cellu-
lar DNA (Sommadossi, Carlisle & Zhou, 1989; Som-
madossi, 1993). Of the purine and pyrimidine analogs
that deactivate HIV in vitro, AZT has been found to
be the most toxic to colony formation by bone marrow
precursor cells. Yet 5 to 7-fold more toxic than AZT
is its metabolite, 3'-amino-3'-deoxythymidine (AMT),
formed both in vivo and in vitro, which may contribute
significantly to AZT's toxicity (Stagg et al., 1992).
The stromal cells within the bone marrow, an essen-
tial microenvironmental component, are sensitive to
AZT in concentrations that occur in the plasma of
patients undergoing AZT therapy. The toxicity of AZT
applied in clinical concentrations to fibroblastoid stro-
mal colonies has been demonstrated in murine bone
marrow cell cultures (Luster et al., 1989). The viabil-
ity of the cells themselves rather than just production
of a growth factor appears to be affected. The concen-
trations of AZT that produced toxic effects in these
in vitro studies are similar to those found in the plas-
ma of AZT therapy recipients, typically 1-5 JLM (Piz-
zo et al., 1988). Damage to stromal cells as a result
of AZT therapy would be especially harmful to long-
term therapy recipients, as is more likely in the case of
asymptomatic persons with CD4+ cell counts of 500-
800/mm3 than in those with lower CD4+ cell counts.
The effects of damage to stromal cells over long peri-
ods on hematopoietic functions of bone marrow could
be long-lasting. Bone marrow hypocellularity has been
shown to persist for as long as 10 weeks after AZT ther-
apy has been halted (Gill et al., 1987; Mir & Costello,
1988).
Biopsies of the bone marrow of patients with AIDS
and ARC reveal a high degree of irregular cell mor-
phology, benign lymphoid aggregates and granulomas
(Spivak, Bender & Quinn, 1984; Namiki, Boone &
Meyer, 1987). Patients with AIDS or ARC are found
to have a significant reduction of growth ofhematopoi-
etic progenitor cells in vitro by comparison with nor-
mal controls (Stella, Ganser & Hoelzer, 1987). These
abnormalities may not be limited to patients with AIDS
or ARC; otherwise asymptomatic HIV+ patients may
also have them, although to a lesser degree. It is like-
ly that these abnormalities would be amplified by the
134
use of AZT with effects that would increase with dura-
tion of its use, as indicated by the results of laboratory
studies.
Methods
European-Australian Group Collaborative Study
The EAGCS included 993 participants from 56 cen-
ters in Europe and Australia who were my seropos-
itive and asymptomatic with a minimum CD4+ cell
count of 400/mm3 • Patients were randomly assigned
double-blind either to the AZT or the placebo group.
Those in the AZT group received 500 mg of AZT
twice daily at 12 h intervals for up to 3 years, depend-
ing on whether their CD4+ counts dropped below 200
cells/mm3 . Participants were stratified according to
baseline CD4+ cell counts: 400-499, 500-749, and
~ 750/mm3 • In addition to AIDS (Centers for Disease
Control, 1987) or severe ARC (Cooper et aI., 1993),
the EAGCS reported benefits to AZT therapy com-
pared with placebo for three other clinical endpoints:
CDC group IY disease (Centers for Disease Control,
1986), CD4+ count> 350/mm3, clinical my disease
and a fifth endpoint, defined as any of the other four
(Cooper et al., 1993). Participants were evaluated for
the efficacy of AZT therapy on the progression to these
clinical endpoints. A full description of the EAGCS is
given in the original report (Cooper et aI., 1993). In
the analysis I now present, Fisher's exact test (Siegel,
1956) is applied in separate CD4+ cell count strata to
evaluate whether AZT therapy and the endpoints of the
study are significantly associated within the strata with
CD4+ counts 500-749 and ~ 750/mm3.
San Francisco Men's Health Study
Study group description
The study group selected from the SFMHS cohort for
this analysis consisted of 212 my seropositive men
who had not progressed to AIDS (Centers for Disease
Control, 1987) and whose CD4+ cell counts were in
the range 200-8oo/mm3 at the first examination cycle
of the study period used in this analysis, early 1987 to
early 1991, including nine examination cycles at six
month intervals. These were the only selection crite-
ria. Four participants were excluded for missing data.
Participants were classified by their exposure to AZT
therapy dichotomously, yes or no, which, therefore,
does not take into account the possible influence of
duration and dose of AZT therapy or compliance of the
participants who are classified as receiving AZT ther-
apy. Those who initiated AZT therapy after they were
diagnosed with AIDS were included in the study risk
set but classified as receiving no AZT therapy. For this
analysis the group was divided into two strata accord-
ing to CD4+ cell counts as baseline of, 200-499/mm3
and 500-800/mm3, with 120 and 92 participants in the
respective strata.
The SFMHS is a prospective cohort study of a
population-based sample of 1034 men that began in
1984 and has been ongoing since then. Participants in
the SFMHS are each given a physical examination at
six month intervals in the study clinic, where exam-
ples are taken for laboratory analysis, including the
measurement of CD4+ lymphocyte counts. The partic-
ipants are given detailed interviews including written
questionnaires that are conducted by the University
of California, Berkeley, Survey Research Center staff.
The procedures for obtaining this population sample,
the collection of data, laboratory and statistical meth-
ods have been fully described (Winkelstein et at., 1987;
Lang et aI., 1987), as have the procedures for deter-
mining serologic status of the participants (Levy et aI.,
1984; Kaminsky et al., 1985.
Statistical methods
Survival methods are used when participants differ in
the duration for which they remain in the study; their
follow-up times may vary for a number of reasons. For
this analysis of the SFMHS data, survival is defined as
not having progressed to AIDS (Centers for Disease
Control, 1987). Survival analysis was applied to the
SFMHS data to assess the effect of AZT therapy on pro-
gression to AIDS (Centers for Disease Control, 1987),
the endpoint of this study. Survival functions, the pro-
portion surviving with time, months since the onset of
this study for participants taking AZT and for those not
taking AZT are plotted. The Kaplan-Meier method was
used to estimate survival functions (Lee, 1980). These
functions are then compared and tested for whether
their difference is statistically significant. 2
In addition to AZT, other variables or covariates
may affect the outcome of progression to AIDS. The
effects of the covariates age, race and recreation-
al drug use and the interaction between AZT thera-
2 An observed association might well occur by chance. The result
of a test of association is a probability level or p-value. A value of
p < 0.05 indicates that there is less than a 5% probability that the
observed association occurred by chance; the association is then said
to be statistically significant.

py and CD4+ count on the endpoint, progression to
AIDS, were evaluated by means of the Cox propor-
tional hazards model, a multivariate regression model
that accounts for varying follow-up times, and includes
the effects on the outcome of the treatment variable and
other explanatory variables, or covariates (Cox, 1972).
The risk of progression to AIDS for any set of values
of the covariates may be calculated with this method.
In addition to CD4+ cell counts and AZT therapy, all
other covariates that were introduced into the propor-
tional hazards model were dichotomous: race, either
white and non-hispanic or all others; age, either < 25
years or 2: 25 years at the beginning of the SFMHS,
and recreational use (yes or no) at entry to the SFMHS
of any of the following drugs: poppers, cocaine, MDA,
psychedelics (e.g., PCP, LSD), downers (e.g., barbitu-
rates, tranquilizers), ethyl chloride, heroin or uppers
(e.g. amphetamines). Calculations were performed
with SAS statistical analysis software (SAS Institute,
1993).
Biases
Dates of first seropositive tests for HIV were known
only for those who seroconverted after entry into the
SFMHS, 20 of the 212 in this study. The analysis of the
SFMHS data could not, therefore, control for incuba-
tion period, which could differ between AZT therapy
yes and no groups. Those HIV+ men who received
AZT therapy, although not yet given a diagnosis of
AIDS, could be more advanced in illness, having sero-
converted earlier than those who did not receive treat-
ment. This difference might not be affected by CD4+
cell counts, which were not different for those given
AZT therapy and those who were not (Table 2). The
application of CD4+ cell count as a measure of clinical
AIDS progression has been questioned (Choi et ai.,
1993; Schechter, Harrison & Halsey, 1994). Another
possible bias rests with the exclusion from this study
of those who seroconverted earlier and/or progressed
rapidly to AIDS before the availability of AZT, thereby
leaving a restricted sub-population for inclusion in the
study.
Results
The European-Australian Group Collaborative
Study
The numbers of subjects in the baseline CD4+ cell
count ranges, 500-749/mm3 , 2: 750/mm3 and the com-
135
bined group from both ranges, 2: 500/mm 3 that were
given AZT or placebo and progressed to each inde-
pendent end point and the percent of the total number
of subjects given AZT or placebo in each cell count
group are presented in Table lA-C (Cooperetai., 1993,
Table 3). Statistical analyses of the published data of
the EAGCS by CD4+ cell count range were performed
to test the conclusion of the EAGCS that AZT therapy
is effective in delaying the onset of clinical symptoms
of AIDS when given to those with baseline CD4+ cell
counts 2: 500/mm3 • The results of the analysis do not
indicate that there is a statically significant association
between AZT therapy and progression to any of the
four independent endpoints of the EAGCS for either
of the CD4+ cell count ranges, 500-749/mm3 (Table
lA) or 2: 750/mm3 (Table IB). Nor does the analysis
indicate a statistically significant association between
AZT therapy and progression to any of the four inde-
pendent endpoints for the combined group, with CD4+
cell count range 2: 500/mm 3 (Table 1C).
The San Francisco Men's Health Study
Descriptive characteristics o/participants selected
from the SFMHS
The study group was largely non-hispanic white (87%)
and entirely homosexual or bisexual. All were between
the ages of 27 and 56 (mean - 37 ± 6.2) at the begin-
ning of the study period of this analysis. Upon entry
into the SFMHS in late 1984,92% reported that they
used recreational drugs, marijuana not included. With-
in this study period 51 % of the study group received
AZT therapy during one or more examination cycles
and 47% progressed to AIDS. The variables age, recre-
ational drug use and racial composition were similar
in both CD4+ cell count strata. The mean values of the
CD4+ cell counts for the lower (200-499) and high-
er (500-800) strata were 383 ±75/mm3 and 652 ±
84/mm3 , respectively (Table 2).
Within both CD4+ cell count strata the demograph-
ic and clinical characteristics of the groups that did and
did not receive AZT therapy were similar; any differ-
ences were not statistically significant (Table 2).
AZT therapy and progression to AIDS
Progression to AIDS occurred in 57% and 34% of
the 200-499 and 500-800 CD4+ cells/mm3 strata par-
ticipants, respectively (Table 2). The probabilities of
progression to AIDS at 30 months (Kaplan-Meier esti-
mates) in the 200-499 CD4+ group were 0.11 and
0.49 for those taking AZT and those not taking AZT,
136

Table 1. Association between AIr treatment and end points in the European Aus-
tralian Group Collaborative Study.

A. Baseline CD4+ cell counts range: 500-749/mm3

Number (%)*
Endpoint AIr Placebo Risk ratio P-value t
I
AIDS or severe ARC 5(2) 6(3) 0.67 0.549
CDC group IV disease 8(3) 14(7) 0.43 0.0489§
CD4+ cell count < 350/mm3 33(14) 42(20) 0.70 0.0584
Clinical HIV disease 21(9) 32(15) 0.60 0.0571

B. Baseline CD4+ cell counts range: ~ 750/mm3

Number (%)*
Endpoint AIr Placebo Risk ratio P-value t
AIDS or severe ARC 0 3(2) 0.00 0.294
CDC group IV disease 1(1) 3(2) 0.50 0.477
CD4+ cell count < 350/mm3 5(4) 9(7) 0.57 Q.411
Clinical HIV disease 4(3) 8(6) 0.51 0.377

C. Baseline CD4+ cell counts range: all ~ 500/mm3

Number (%)*
Endpoint AIr Placebo Risk ratio P-valuet
AIDS or severe ARC 5(1.5) 9(2.6) 0.57 0.420
CDC group IV disease 9(2.5) 17(4.8) 0.51 0.110
CD4+ cell count < 350/mm3 38(10.5) 51(15.0) 0.70 0.0883
Clinical HIV disease 25(6.8) 40(11.5) 0.59 0.0369§

*Data reproduced from Table 3, Cooper et al., 1993.

tEvaluated by Fisher's exact test, 2-tailed (Siegel, 1956).
§The EAGCS results involve multiple comparisons; the statistical significance of
this association is, therefore, questionable.

Table 2. Demographic and clinical characteristics of SFMHS groups.

CD4+ 200-499/mm3 CD4+ 500-800/mm3

AZTyes AZTno Stratum AIr yes AIr no Stratum

Number of subjects 68 (57%) 52 (43%) 120 41 (45%) 51 (55%) 92

Mean CD4 cell count 390 ± 76 375 ± 73 383 ±75 636 ±75 664±9O 651 ± 84
Progression to AIDS 47% 62% 57% 41% 27% 34%
Recreational drug use 93% 89% 91% 93% 94% 93%
White (non-hispanic) 88% 88% 88% 93% 80% 86%
Mean age 37.6 ±6.2 37.9 ±7.0 37.7 ±6.5 36.9 ± 5.8 35.9±5.6 36.3 ±5.7

respectively (95% confidence interval for the differ-
ence, -0.38, -0.58 -0.18). In the 500-800 CD4+-
group these probabilities were not significantly differ-
ent, 0.125 and 0.121 for those taking AZT and those
not taking AZT, respectively.
The risk ratio for progression to AIDS for those
receiving AU therapy compared with those who did
not was 0.33 (95% confidence interval 0.20-0.55)3 in
the 200-499 CD4+- cellslmm3 and 0.87 in the 500-
800 CD4+- cellslmm3 stratum (95% confidence interval
3 The 95% confidence interval or confidence limits is the range
within which the true value or population mean lies with 95% proba-
bility as determined from the sample being studied. If the confidence
interval of a risk ratio contains the value 1, the risks are not signifi-
cantly different.

Table 3. Risk ratios for progression to AIDS, AZT YES vs. AZT NO within SFMHS CD4+ cell
count groups.
CD4+ cell count P-value§
200-499/mm3 0.00014
500-800/mm3 0.8*,O.7 t
200-800/mm3 0.006*,O.002 t
* Wilcoxon test.
tLog-rank test.
:j: Maximum likelihood estimates, proportional hazards model.
§Estimates from Kaplan-Meier survival analysis.
0.32-2.41). The relative risk for progression to AIDS
for the entire study group was 0.55 (95% confidence
interval 0.37-0.SS) (Table 3).
Interaction between AZT and CD4+ cell count
Survival functions from Kaplan-Meier estimates for
those taking and those not taking AZT are shown for
the two CD4+ cell count strata in Figures lA and
lB. These functions show the fraction of those who
have not developed AIDS as a function of time in
months from the study baseline. The survival func-
tions in the 200-499 CD4+ cell count stratum of the
AZT ~ yes and AZT = no groups are significantly dif-
ferent (p - 0.0001) (Fig. 1A), whereas they are not
significantly different in the 500-S00 CD4+ cell count
stratum (p - 0.7) (Fig. lB), indicating there is a hetero-
geneity between the two CD4+ cell count strata. Sur-
vival functions for those taking AZT and those not tak-
ing AZT for the entire study group, CD4+ cell counts
200-S00/mm3, are significantly different (Table 3).
This heterogeneity suggests the possibility of an
interaction between AZT therapy and a covariate, or
explanatory variable. The significance of covariates
and covariate-AZT therapy interaction for the risk of
progression to AIDS with time was examined with the
Cox proportional hazards model, a log-linear regres-
sion model (Cox, 1972). The model which fits the data
best, by maximum likelihood criteria, includes an inter-
action between AZT therapy and baseline CD4+ cell
count category as well as baseline CD4+ cell count
category and AZT therapy as explanatory variables.
Other variables that were tested - race, recreational
drugs use and age - were not significant variables in
the model. If the interaction term is not included, the
model is inadequate.
The survival functions for progression to AIDS for
separate CD4+ cell count strata and AZT yes or no
137
Risk ratiot 95% Confidence limitst P-value t
0.33 0.20-0.55 <0.0001
0.87 0.32-2.41 0.8
0.55 0.37-0.80 0.007
treatment groups that were calculated with this model
(Fig. 2C, D) are similar to the survival functions pro-
duced by Kaplan-Meier estimates (Fig. 2A, B). The
difference between survival functions for AZT yes and
no groups within the 200-499 cell count stratum is
statistically significant, but that within the 500-S00
CD4+ cell count stratum, where the survival functions
are nearly overlapping, is not (Table 3).
Case history: an HN+ asymptomatic patient
receiving AZT therapy
A detailed set of unpublished clinical observations,
including CD4+ cell counts, for an mv+ and initially
asymptomatic patient has been provided by D. Roise
(unpublished). A patient found to be mv seropos-
itive and followed until death 45 months later was
monitored for CD4+ count levels at frequent intervals
before and during AZT therapy (Fig. 2). The patient
was entirely asymptomatic when initially testing pos-
itive for mv. AZT therapy was initiated 20 months
later. The AZT dosage prescribed was 800 mg/day.
The initial symptom of AIDS, extreme fatigue, was
reported only after receiving AZT therapy for two
months. Symptoms of thrush occurred after CD4+
counts dropped below 200. The patient subsequently
developed a mycobacterial infection, first diagnosed in
the bone marrow at which time it was overwhelming.
Measurements of other blood cell counts gave simi-
lar results: normal before AZT therapy, declining in
number after the start of AZT therapy. Similar stud-
ies on other patients over long periods with frequent
measurements of CD4+ counts, and other variables as
well, could provide essential information regarding the
toxicity and the effects of AZT.
138

KAPLAN-MEIER ESTIMATES

200-499 CELLS I CU. MM. 500-800 CELLS I CU. MM.

A 8
1.0

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iii p=O.7

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1.0 ~
0
0
'0
DO 0 !tJ p=0.OOO1 0
0
0

'
0.8 ~ 0.8
o
B
'\, c tJ

.
• '0
'., 00 .!!
0.6 ;; 0.6 0
0
...
I!
".. '. 0 0
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0.4 0 ~~
0.4
• 0
0 III
• 0 0
0.2 0 0.2
0
AZT NO 0

.
o o AZT NO 0
o AZT YES 0
0.0 0 0.0 o AZT YES 0

0 10 20 30 40 50 60 70 a 10 20 30 40 50 60 70
TIme (month.) TIme (months)

Cox PROPORTIONAL HAZARDS MODEL

200-499 CELLS I CU. MM. 500-800 CELLS I CU. MM.

\
C D
1.0 ............... 1.0 p=O.B
p<0.OOO1
..........
-,
O.B '" O.B
0
c .......... c:
.2
:;::
U
u
...E
0.6
...c
"-
0.6

c> C
>
'E 0.4 .~
0.4
::J
VI ::I
Vl
0.2 0.2

0.0
- AZT NO
.••• -- AZT YES
. 0.0
- - AZT NO
.----- AZT YES

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
TIme (months) Time (months)

Fig. 1. Proportions of subjects who have not progressed to AIDS as a function of time elapsed from baseline. Survival function plots from
Kaplan-Meier estimates (A & B) and Cox proportional hazards model (C & 0). (A & C): baseline C04+ cell counts 200-499/mm3 (B & 0):
baseline C04+ cell counts 500-800/mm3 •

Discussion ses indicate some benefit from AZT treatment in terms

of progression to AIDS for participants in both studies
These analyses of data from the SFMHS, an observa- whose CD4+ cell counts are < SOO/mm3 , quality of life
tional cohort study, and the EAGCS, a double-blind variables were not considered; these have been shown
placebo-controlled clinical trial, indicate there are no to cancel benefits of AZT therapy in terms of progres-
benefits from AZT therapy in terms of progression to sion to AIDS for those who are HIV + and asymptomat-
AIDS for those who are asymptomatic and have CD4+ ic with CD4+ cell counts in the range 200-S00/mm3
cell counts that are 2: SOO/mm3 • Although my analy- (Lenderking et at., 1994).

700.---.----.---.----.---~---r----
600
--full dose
AZr sfarted
E 500
~
Low dose->
E
AZT sfarted r->
flrsf AIDS
sympfoms
C 300
"o
u
C!; 200
u was not significantly different from those who did not
100
oL-__ ~ __ ~ __- L_ _ ~_ _~_ _ _ _~~
o 6 12 18 24 30 36
Durafion (monfhs)
Fig. 2. CD4+ cell counts in an mv+ initially asymptomatic patient
before and during AZT treatment.
Different interpretations ofAZT prophylaxis in the
EAGCS
The EAGCS report concluded that the study provided
the first demonstration of the beneficial effect of AZT
prophylaxis in terms of progression to AIDS when
taken by persons who are mv+ and asymptomatic for
AIDS and whose CD4+ cell counts are ~ 500/mm3
(Cooper et al., 1993). I have analyzed the reported
EAGCS data by CD4+ cell count strata, 500-7 49/rnm3,
~ 750/mm 3 and ~ 500/mm3, instead of, as was done in
the EAGCS report, for all participants in the EAGCS,
unstratified, who were selected by the criterion that
their baseline CD4+ cell counts be ~ 400/mm 3•
The EAGCS reported statistically significant over-
all risk ratios for those given AZT relative to placebo
of 0.49-0.60 for progression to 3 of the 4 independent
study endpoints, the exception being that of AIDS or
severe ARC, in which case the risk ratio was not statis-
tically significant. Because they did not perform sepa-
rate tests for statistical significance by baseline CD4+
cell count strata, 500-749, ~ 750 or overall above
500/mm 3 , the analysis presented by the EAGCS cannot
support its claim to demonstrate the beneficial effects
of AZT on progression to AIDS and other endpoints
of the study in participants with baseline CD4+ cell
counts ~ 500/mm3 • My analysis of the EAGCS data by
separate strata demonstrates that associations between
AZT therapy and the endpoints of the EACGS for the
139
separate CD4+ cell count strata 500-749, ~ 750 and
~ 500/mm 3 are not statistically significant; therefore
my analysis does not agree with their conclusion that
AZT reduces the risk of progression to AIDS or other
clinical endpoints of the EAGCS for patients whose
baseline CD4+ cell counts are ~ 500/rnm 3•
AZT prophylaxis for SFMHS participants by CD4+
cell count strata
The participants of the SFMHS with baseline CD4+
counts in the range 500-800/mm 3 who received AZT
therapy progressed to AIDS with a probability that
receive AZT therapy, confirming the results of my
analysis of the EAGCS data for participants of that
study with baseline CD4+ cell counts ~ 500/mm 3 •
42 The analysis of the SFMHS data is performed with
survivorship methods: (1) Kaplan-Meier product limit
estimates for separate baseline CD4+ cell count groups,
200-499/rnm3 and 500-800/rnm3, testing for the dif-
ference between survival from progression to AIDS of
those who do receive AZT treatment and those who
do not, and (2) the Cox proportional hazards model
for the relative risk of progression to AIDS in terms of
regression coefficients of covariates: AZT treatment,
baseline CD4+ counts and an interaction between these
two variables. Survivorship results from the Kaplan-
Meier estimates agree with those of the Cox model
only if the latter includes the interaction between AZT
and baseline CD4+ cell count, which accounts for the
inhomogeneity in the effect of AZT treatment between
the two CD4+ cell count groups, while AZT treatment
provides a statistically significant benefit in terms of
progression to AIDS for the entire study group.
Interaction between treatment and an explanatory
variable is suggestive of biological differences between
different strata, such as the nature of the disease process
or stage, which modifies the effect of the treatment.
Demographic characteristic of the SFMHS participants
in the two strata did not differ (Table 2). The differing
CD4+ cell counts suggest that differences which would
alter the effect of AZT upon progression to AIDS by
participants in the two strata rest with the effects of
AZT upon the integrity of the immune system and is
the result of the hematopoietic toxicity of AZT that has
been demonstrated in clinical and laboratory studies.
The immune systems of those with CD4+ cell counts
of 500-800/rnm3 might be damaged to a greater extent
relative to those with CD4+ counts of 200-499/mm 3
by the toxicity that results from AZT therapy.
140
This study does not address the use of medica-
tion prophylactically for AIDS-related diseases, e.g.,
Pneumocystis carinii pneumonia, that could delay pro-
gression to AIDS and thereby provide an apparent
benefit of AZT therapy (Osmond et al., 1994). Fur-
ther, participants taking AZT might have modified
their behavior in ways that would favorably affect their
health and possibly delay progression to AIDS, such
as an improved nutrition (Abrams, Duncan & Hertz-
Piccioto, 1994) or decrease in smoking, alcohol con-
sumption or recreational drug use during the course of
AZT treatment, factors which were not accounted for
in this analysis. These biases could underlie the appar-
ent benefits of AZT in terms of progression to AIDS
and possibly the heterogeneity of the efficacy of AZT
between the two CD4+ cell count strata.
The cumulative toxic effects of AZT upon
hematopoiesis that has been demonstrated in the lab-
oratory, with typical clinical plasma concentrations of
AZT, may be responsible for the harm in terms of qual-
ity of life which renders treatment with AZT to be of
no benefit to asymptomatics with CD4+ cell counts of
200-500/mm 3 (Lenderking et aI., 1994). It is likely that
AZT should have similar effects upon the quality oflife
of HIV seropositive persons with CD4+ cell counts in
the ~ 500/mm3 range, and, further, that toxicity plays
a significant role in AZT's providing no benefit for this
group in terms of progression to AIDS, as demonstrat-
ed by these analyses of the EAGCS clinical trial and
SFMHS obversational cohort data.
In the Concorde trial, the temporary advantage for
the immediate group has been attributed to the develop-
ment of viral resistance. The cumulative hematological
toxicity of AZT might well also contribute to its longer
term ineffectiveness. Cumulative toxic effects of AZT,
in terms of shortening life, could outweigh any gains
achieved over the short term for progression to AIDS.
Deaths in the Concorde trial after 3 years were 9.0%
of the immediate and 7.7% of the deferred groups, not
statistically significant. Peto and Collins (1993) have
raised this issue with reference to viral resistance and
strongly suggest larger and longer duration studies as
well as meta-analysis of all placebo-controlled trials to
enable a definitive assessment of AZT's benefits with
regard to its effect on duration of life.
Acknowledgements
I wish to thank Professor Peter Duesberg for his help-
ful criticisms and suggestions and Professor Richard
Strohman for his advice and encouragement. Dr. Dou-
glas Roise, St. Joseph's Hospital, Dickenson, N.,
Dakota, generously allowed his unpublished clinical
AZT data to be presented here. Alan Downey and
Bryan Ellison were unfailingly helpful in obtaining
pertinent data files, with the cooperation of Dr. Eric
Vittinghoff. I am much indebted to the researchers and
staff of the San Francisco Men's Health Study, who
have worked many years to assemble the data of the
cohort. Data from the SFMHS cohort was obtained
under contract between the Regents of the Universi-
ty of California and the National Institutes of Health,
NOI-AI-82515.
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© 1996 Kluwer Academic Publishers.

The toxicity of azidothymidine (AZT) on human and animal cells in culture

at concentrations used for antiviral therapy

David T. Chiu & Peter H. Duesberg

Dept. of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA

Received 10 October 1994 Accepted 11 November 1994

Key words: chemotherapy, discrepancies in cytotoxic dose, AZT-resistant cell variants

Abstract

AZT, a chain terminator of DNA synthesis originally developed for chemotherapy, is now prescribed as an anti-
human immunodeficiency virus (HIV) drug at 500 to 1500 mg/person/day, which corresponds to 20 to 60 J.LM AZT.
The human dosage is based on a study by the manufacturer of the drug and their collaborators, which reported in
1986 that the inhibitory dose for HIV replication was 0.05 to 0.5 J.LM AZT and that for human T-cells was 2000
to 20,000 times higher, i.e. 1000 J.LM AZT. This suggested that HIV could be safely inhibited in humans at 20 to
60 J.LM AZT. However, after the licensing of AZT as an anti-HIV drug, several independent studies reported 20-
to 1000-fold lower inhibitory doses of AZT for human and animal cells than did the manufacturer's study, ranging
from 1 to 50 J.LM. In accord with this, life threatening toxic effects were reported in humans treated with AZT at
20 to 60 J.LM. Therefore, we have re-examined the growth inhibitory doses of AZT for the human CEM T-cell line
and several other human and animal cells. It was found that at 10 J.LM and 25 J.LM AZT, all cells are inhibited at
least 50% after 6 to 12 days, and between 20 and 100% after 38 to 48 days. Unexpectedly, variants of all cell types
emerged over time that were partially resistant to AZT. It is concluded that AZT, at the dosage prescribed as an
anti-HIV drug, is highly toxic to human cells.

Introduction Since 1987, chronic administration of AZT and

AZT (3'-azido-3'-deoxythymidine) is an analog of
thymidine in which the 3' hydroxyl group is replaced
by an azido group. This prevents the extension of a
growing DNA strand ending with AZT to the five
prime end of another nucleotide triphosphate. Thus
AZT functions as a chain terminator of DNA synthe-
sis.
AZT was originally designed in the 1960s to be
used as chemotherapy for leukemia (Horwitz, Chua
&Jol"oel, 1964). The rationale for cancer chemothera-
py is to kill cancer cells during mitosis with cytotoxic
chemicals like AZT. Because chemicals cannot dis-
tinguish cancer cells from normal cells, the price for
chemotherapy is the death of normal cells that are in
mitosis. Therefore, chemotherapy must be restricted
to days or weeks. Successful chemotherapy kills the
cancer before it kills the host.
similar nucleoside analogs, like ddC and ddI, have been
prescribed to AIDS patients to inhibit human immun-
odeficiency virus (HIV), the presumed cause of AIDS
(Fischl et al., 1987; Richman et al., 1987; Yarchoan et
al., 1991). Since 1990, AZT has also been prescribed
to healthy HIV antibody-positive persons to prevent
AIDS (Volberding et al., 1990; Tokars et al., 1993;
Seligmann et al., 1994). The rationale is to inhibit
HIV DNA synthesis at doses that do not inhibit cell
DNA synthesis (Yarchoan et al., 1991). It is claimed
by Burroughs-Wellcome, the manufacturer of AZT,
and its collaborators that this can be achieved, because
AZT would inhibit DNA synthesis with HIV DNA
polymerase in vitro 100 times more effectively than
DNA synthesis with cellular DNA polymerase (Fur-
man et al., 1986). Moreover, this study claimed that in
vivo AZT was 2000 to 20,000 times more inhibitory
to HIV replication, i.e. at 0.05 to 0.5 J.LM, than to cell
division, i.e. at 1000 J.LM (Furman et at., 1986).
144
Accordingly, anti-HIV doses of An were chosen
to fall into this therapeutic window, e.g. to be 500 to
1500 mg per person per day, or about 20 to 60 pM per
kg per day (Furman et al., 1986; Fischl et al., 1987;
Volberding et al., 1990; Physicians' Desk Reference,
1994).
However, in view of its inherent cytotoxicity, AZT
has been questioned as an acceptable anti-HIV drug on
three theoretical grounds (Duesberg, 1992):
(i) Even if AZT were to inhibit HIV DNA synthesis
100 times more than cell DNA synthesis, it could
not 'selectively' inhibit mv, as is claimed by the
manufacturer (Furman et al., 1986). Since HIV
DNA measures only 10 kb and cell DNA measures
106 kb, and since both DNAs are made in vivo
simultaneously inside the same cell, cell DNA pro-
vides a lOS-fold bigger DNA target for AZT toxi-
city than does HIV DNA. Therefore, the 100-fold
higher selectivity of AZT claimed for HIV DNA
synthesis is immaterial.
(ii) Inhibition of HIV DNA synthesis in mv-
antibody positive persons is completely unneces-
sary, because HIV does not spread in the pres-
ence of antiviral antibody (Duesberg, 1992). It is
for this reason that only about 1 in 1000 T-cells
is ever infected in mY-antibody positive persons
(Duesberg, 1992). The fact that '. mly about 0.1 %
of all susceptible T-cells are ever infected by HIV
in HIV-positive persons with and without AIDS
proves that HIV is very effectively neutralized by
antiviral immunity. Moreover, there is no corre-
lation between the number of HIV-infected cells
and AIDS (Duesberg, 1993; Piatak: et al., 1993).
For example, there are healthy HIV-positive per-
sons who have 30 to 40 times more HIV-infected
cells than AIDS patients (Simmonds et al., 1990;
Bagasra et al., 1992; Duesberg, 1992).
(iii) Since only about 1 in 1000 T-cells are ever infected
by HIV in persons with or without AIDS (Dues-
berg, 1992; 1992), AZT must kill 999 uninfected
cells in order to kill just one HIV-infected cell - a
very poor pharmacological index.
Thus theory predicts that AZT cannot selectively
restrict HIV replication in vivo. AZT can only inhib-
it HIV by killing infected and uninfected target cells.
Theory further predicts that AZT is unacceptable as
anti-HIV therapy in mY-antibody positive persons,
because it will kill 999 uninfected cells for every infect-
ed cell.
In response to these theoretical considerations it is
argued by the manufacturer of AZT and its collabora-
tors that, contrary to expectations, An is an effective
anti-HIV drug, because cell division was observed to
be 2000 to 20,000 timeS more drug-resistant than HIV
replication (Furman et al., 1986).
However, after AZT had been licensed for human
use, several independent studies reported that the drug
is about 20 to 1000 times more toxic to human cells
in culture than the manufacturer had claimed, i.e. that
the half inhibitory doses (ID 50) ranged between 1 and
50 pM (Table 1). In accordance with these results,
life threatening toxicity including anemia, leukopenia,
nausea, muscle atrophy, dementia, hepatitis and mor-
tality, has been documented in humans treated with
20 to 60 pM AZT (Mir & Costello, 1988; Duesberg,
1992; Freiman et al., 1993; Tokars et al., 1993; Bacel-
lar et al., 1994; Goedert et al., 1994; Seligmann et al.,
1994). If these results were correct, both the dosage
of AZT prescribed to humans and the advisability of
AZT as an anti-HIV drug need to be reconsidered.
In view of up to a 1000-fold discrepancy between
the cytotoxicity of AZT reported by the manufactur-
er and his collaborators (Furman et al., 1986) and the
cytotoxicities reported by other investigators (Table 1),
we set out to redetermine the cytotoxicity of AZT. We
have investigated the effects of AZT on the human
CEM T-cell line and on several other human and ani-
mal cells in culture. In contrast to the previous studies,
that measured toxicity over 1 to 3 rounds of mitoses,
we decided to measure long-term toxicity over sever-
al weeks, representing up to 24 consecutive cell divi-
sions. We reasoned that this experimental design would
more closely mimic human exposure, which is indef-
inite, extending over numerous mitoses (Fischl et al.,
1987; Volberding et at., 1990; Physicians' Desk Ref-
erence, 1994). Under the conditions AZT is prescribed
as an anti-HIV drug, i.e. chronic application, it could
indeed be more toxic than it is after only one or a few
mitoses studied earlier, because non-lethal mutations
would accumulate in surviving cells. Our experimen-
tal design would detect cumulative mutational toxicity
acquired over several mitoses, in addition to the com-
plete cytotoxicity observed in one or a few mitoses.
Materials and methods
Materials. RPMI 1640 medium, Dulbecco's Modified
Eagle's medium, and fetal bovine serum were pur-
chased from Gibco Laboratories (Grand Island, NY).
Serum Plus was purchased from JRH Biosciences
 145

Table 1. 50% inhibitory dose of AZT for human and animal cells as reported
by various laboratories.

Study Cell type IDso at 11M AZT

(Furman et al., 1986) human T-cell, line H9 1000

(Balzarini, Herdewijn human T-cell, line CEM >1000
& De Clercq, 1989)
(Mansuri et al., 1990) human T-cell, line CEM 54
(Lemaitre et al., 1990) human T-cell, line CEM 36
(Avramis et al., 1989) human T-cell, line CEM 4
(Sommadossi et al., human bone marrow 1
1990) human bone marrow 5
(Inoue et al., 1989) human bone marrow 5
human bone marrow 25
(Mansuri et al., 1990) mouse bone marrow 1.5
(Gogu, Beckman & mouse bone marrow 2
Agrawal, 1989) mouse fetal liver

(Lenexa, KS). AZT was purchased from Sigma Chem-
ical Co. (St. Louis, MO).
Culture conditions of cells grown in suspension.
The CEM human lymphoid T-cell line was provid-
ed by Robert F. Garry, Tulane University School of
Medicine, New Orleans, LA. CEM T-cells were sus-
pended in 5 mL of RPMI 1640 medium enriched with
10% Serum Plus in tissue culture flasks (25 cm2 growth
area, Falcon) and were propagated at 37°C in humidi-
fied air with 6.5% C02. The CEM T-cells were main-
tained at a density around 3 x 105 cells per mL by dilut-
ing them 1:2 every other day. The medium was changed
every day by spinning down the cells for 5 min in a
clinical centrifuge at 6000 rpm and then resuspending
them in fresh medium. AZT was added twice every
day at 10 and 25 j.lM concentrations by micropipets
with sterile tips. AZT additions were made at about
12 h intervals. A control flask of CEM T-cells was
passaged identically without the addition of AZT. A
10 j.lL aliquot of evenly distributed cells was counted
every other day with a hematocytometer.
Culture conditions of cells grown attached to Petri
dishes. The C3H mouse fibroblast cell line, the Hs-27
human foreskin cell line and the WI-38 human lung cell
line were purchased from the American Type Culture
Collection. The secondary Chinese Hamster lung cells
were prepared from animals in our lab. Each of these
cell types was cultured while attached to Petri dishes
(100 x 20 mm, Falcon) in 10 mL of Dulbecco's Mod-
ified Eagle's medium enriched with 10% fetal bovine
serum at 37°C in humidified air with 6.5% CO 2 , Each
of the monolayer cell types was seeded of approximate-
ly 1 x 105 cells on a lO-cm dish containing 10 mL of
medium. The medium in each dish was changed every
day. AZT additions were also made twice a day at
10 and 25 j.lM concentrations. The cells were counted
with a Coulter counter by placing a 200 j.lL sample of
evenly distributed cells in 10 mL of isotonic buffered
saline solution. Each AZT-treated culture was split 1:5
when the control dish had reached 100% confluency.
Results
The effect of long-term AZT treatment on the viabil-
ity of the human CEM T-cell line. To determine the
cytotoxicity of AZT on the human CEM T-cell line in
culture, parallel cultures were incubated with 10 j.lM,
25 j.lM AZT and withoutAZT (see Materials and meth-
ods). The untreated cells were maintained at saturation
density of CEM cells, which is about 3 x 105 cells per
mL in our conditions. Each culture was divided 2-fold
every 48 h, by which time the AZT-free control had
regained saturation density.
As can be seen in Fig. 1, after four days the cell
count of the culture at 25 j.lM AZT had been reduced
to half of the control, and that of the culture at 10 j.lM
AZT to two thirds of the control. After 12 days the
cell densities of both AZT-treated cultures had been
146
4~-------------------------------------'
Fig. 1. The effect of AZT, at 10 J.IM and 25 J.IM, on the growth rate of the human CEM T·cellline maintained as described in the text.
reduced to a third of the control culture. From then on,
the density of the culture at 25 J-LM AZT continued to
decline at a decreasing rate, and that of the culture at
10 J-LM AZT stabilized (Fig. 1).
One possible explanation of the decreasing sensi·
tivity of surviving CEM cells to AZT over time is that
the dividing portion of the cells takes up all AZT in
a short time, and that the resting portion of cells sub-
sequently enters mitosis in a culture depleted of AZT.
Another explanation suggests that variants are selected
that do not incorporate AZT into DNA. To distinguish
between these possibilities each AZT-treated culture
was further divided into two. One of the two sub-
cultures was maintained with daily medium changes
containing 10 and 25 J-LM AZT respectively as before.
The other subculture was supplemented, 12 hours after
the medium including AZT had been changed, with the
equivalent of an extra 10 and 25 J-LM AZT respectively.
All cultures were further incubated under these condi-
tions for anothe( 32 to 36 days.
It can be seen in Fig. 1 that even at two daily
applications of AZT at 10 J-LM, a decreasing fraction of
T-cells retained viability for 14 days (when the culture
became contaminated). However, no survivors were
observed after 14 days at two daily applications of
25J-LMAZT.
It is concluded that T-cell variants are selected, on
long-term exposure to AZT, that are relatively resistant
--0- control
········0·····... 10 J1M AZT
···-0-··· 25 J1M AZT
----6---- 10 J1M AZT (2X/day)
- - -EB- - - 25 J1M AZT (2X/day)
to AZT compared to the average T-cell prior to treat-
ment.
The effect of long-term exposure to AZT on the via-
bility of human and animal fibroblasts. To determine
whether other human and animal cells are similar to
human T-cells with regard to AZT-sensitivity, the via-
bility of a human lung (WI) and foreskin (Hs) cell line,
of a mouse cell line (C3H) and of secondary Chinese
hamster cells (C.H.) was studied in AZT.
Each of the different cell types was seeded at 1 x 105
cells per 10 cm dish and exposed to AZT at 10 and
25 J-LM (see Materials and methods). AZT was added
to each dish twice every day, once in the morning and
again at night as described above. The inhibition of cell
growth was expressed as the percentage of cells in the
AZT culture compared to that of the untreated control.
The cells were counted by the time the control had
reached confluency (Fig. 2). The first count of cells
was taken at the end of two weeks when all control
dishes had become completely confluent. Thereafter
control cells were split 1:4 and allowed to reach con-
fluency again. This process was repeated several times
as shown in Fig. 2.
As can be seen in Fig. 2, the general pattern of
AZT-sensitivity observed with T-cells was confirmed
with other human and animal cells. C3H mouse cells
appeared to be most sensitive to the effects of AZT. At
 147

-e 120

-=
-0- control

········0········ C.H. 10 JiM

~
CJ 100
~
;I
----0---- C.H. 25 JiM
c...
80 ----6---- C3H 10 JiM

..
~

.•=
~
---Bl--- C3H25 JiM

-== 60 _._ -.-. Hs-27 10 JiM

---e---
-
~
CJ Hs-27251lM
~
40
U - - 9- - WI-3810 JiM

20 --4·-- WI-38 25 JiM

0 10 20 30 40

day
Fig. 2. The effect of AZr, at 10 p.M and 25 p.M, on the growth of human lung (WI), and foreskin cells (Hs), on mouse fibroblasts (C3H) and on
secondary Chinese hamster (C.H.) fibroblasts. AZT-treated cells were counted whenever the untreated control culture had reached conftuency.

day 14, the densities ofC3H cells, maintained at both
concentrations of AZT, had already declined to below
50 percent of the control. Possibly due to a counting
error, the density of C3H cells at 10 pM AZT appeared
lower than that of cells at 25 pM AZT. After the same
time, the concentrations of Hs-27, WI-38, and C.H.
cells ranged from 50 to 60 percent of the control at
25 pM AZT, and from 60 to 70 percent of the control
at 10 pM AZT.
From 14 to 38 days of AZT treatment all fibroblast
cells remained at about half the density of the controls.
However, the densities ofC3H and Hs-27 cell lines
gradually increased over time at both concentrations
of AZT. By day 38, the density of Hs-27 cells at both
AZT concentrations had reached up to 80 percent of
the control.
Discussion
(i) AZT toxic to human cells in the micromolar range.
Our results indicate that long-term exposure to AZT
inhibits the growth of human CEM T-cells about 50%
at 10 pM, and gradually up to 100% at ·25 pM. Sim-
ilar results were obtained with human lung and fore-
skin cells, and also with mouse and Chinese hamster
cells, although complete inhibition was not observed
with any of these cells under our conditions. Thus
our results confirm and extend those of others sum-
marized in Table 1, that AZT is toxic to human cells
in the micromolar range. Indeed AZT, like all other
nucleotide analogs of DNA, is expected to be toxic
in the micromolar range, because the Michaelis con-
stants of authentic nucleotide triphosphates are also in
the micromolar range (Kornberg, 1980).
These results are incompatible with the claim of
the manufacturer and its collaborators that AZT is only
toxic to human cells in the millimolar range. That claim
is also hard to reconcile with the manufacturer's own
observation that HIV replication is inhibited by AZT at
0.05 to 0.5 pM (Furman et al., 1986). Since (i) HIV and
cell DNA are both replicated in vivo inside the same
cellular vesicle and at the same time (Rubin & Temin,
1958; Weiss et al., 1985), (ii) retroviral and cellular
DNA synthesis depend on the same triphosphate pools,
and (iii)retroviral DNA is a lOS-fold smaller target for
AZT than cell DNA, HIV DNA synthesis cannot be
more sensitive to AZT than cell DNA. In fact target
theory predicts the opposite.
Thus the preponderance of evidence casts doubts
on the claim of the manufacturer of AZT and its collab-
orators that AZT is only toxic to cells in the millimolar
range (Furman et al., 1986).
148
(ii) Resistance of human and animal cells to long-
term exposure to AZT. Unexpectedly, partially AZT-
resistant variants emerged from human T-cells and all
other cells tested on continued exposure to AZT at 10
to 25 J-lM for 38 t048 days. These variants did not reach
the densities of untreated control cells, but continued
to divide in the presence of AZT at various rates. Fur-
ther work is needed to analyze the basis for the relative
AZT-resistance acquired by human and animal cells
upon long-term exposure to AZT.
(iii) Toxicity ofAZT at micro molar concentrations calls
for reappraisal of its use as ananti-HIV drug. The cell
culture results described by us and others predict that
AZT is toxic to humans at the 20 to 60-micromolar
level, the concentrations at which it is prescribed
as an anti-HIV drug. Even though our results show
that human and animal cells acquire some resistance
against AZT upon long-term exposure, no cell has
achieved complete resistance to AZT under the con-
ditions tested. This prediction is confirmed by numer-
ous clinical studies that describe life threatening toxic
effects in humans treated with AZT at 20 to 60 J-lM
(see Introduction). Thus our data and those of others
call into question the merits of AZT as an anti-HIV
drug, particularly at the doses currently prescribed to
humans.
Acknowledgments
We thank Robert F. Garry, Tulane Univ. New Orleans,
for the human CEM T-cell line and for generous advice,
and Gedge D. Rosson, UC Berkeley, for preliminary
results and discussions. This investigation was sup-
ported in part by the Council for Tobacco Research,
USA, and private donations from Thomas Boulger
(Redondo Beach, Calif., USA), Glenn Braswell (Los
Angeles, Calif., USA), Dr. Richard Fischer (Annan-
dale, Va., USA), Dr. Fabio Franchi (Trieste, Italy), and
Dr. Peter Paschen (Hamburg, Germany).
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Measuring inhalant nitrite exposure in gay men: implications for elucidating

the etiology of AIDS-related Kaposi's sarcoma

Harry W. Haverkos h & D. Peter Drotman2

1National Instituteon Drug Abuse. Rockville. Maryland
2 Centers for
Disease Control and Prevention. Atlanta, Georgia
*Address for correspondence: NIDNNIH. 5600 Fishers Lane. Room lOA-38, Rockville, MD 20857, USA
Received 15 June 1994 Accepted 6 July 1994

Abstract

We reviewed 12 epidemiologic studies conducted among gay men with AIDS to examine the role of potential
'cofactors' in the development of KS. Aspects of the studies reviewed include basic study design, wording of the
questionnaires, and published results comparing KS patients with those who developed opportunistic infections
indicative of AIDS. The studies included questions about sociodemographics, medical history, use of drugs, travel,
and sexual behaviors. Patients were invited to provide blood and/or other specimens for laboratory analysis.
The results of the review of epidemiologic studies are inconclusive. Nitrite inhalant use was a variable often
associated with KS (five studies). The differences in outcomes of these studies may reflect differences in study
designs, sample sizes, timing, quality, and content of interviews regarding nitrites, sexual behaviours and other
potential cofactors. Epidemiologic study with careful consideration to content of questionnaires and laboratory
testing may yet reveal the causes or cofactors for this tumor.

Introduction Methods

The unique epidemiology of Kaposi's sarcoma (KS)
among AIDS patients suggests that the cause of KS in
AIDS is multifactorial (Haverkos, Drotman & Morgan,
1990; Haverkos, Drotman & Hanson, 1993). Although
HIV appears to playa major role in the pathogenesis of
KS, HIV alone is not its cause. At least one cofactor (a
necessary factor and/or an enhancing factor) associated
with gay lifestyle predisposes HIV-infected persons to
KS. A second sexually transmitted organism, a fecal-
orally transmitted organism, genetic predisposition and
nitrite inhalant use have been proposed as cofactors.
In this paper we review the methods and results of
several case-control studies conducted to identify risk
factors for AIDS-related KS among homosexual men.
Our efforts focus on nitrite inhalants because they have
often been identified as a cofactor and the questions
employed to measure nitrite inhalant use are so varied.
We reviewed the epidemiologic studies conducted
among gay men with AIDS to examine the role of
nitrite inhalants and other potential 'cofactors' in the
development of KS. We identified studies by reviewing
the medical literature and International Conference on
AIDS meeting abstract books and personal communi-
cations with investigators interested in the epidemiol-
ogy of AIDS-related KS. An epidemiologic study was
considered if it compared behavioral and laboratory
variables of gay men with AIDS-related KS to those
of gay men with AIDS but with no evidence of KS.
We limited the review to studies published in the med-
icalliterature or in International Conference on AIDS
abstract books by December 31, 1993. We contacted
all principal investigators whose studies met the study
definition and requested a copy of the behavioral ques-
tionnaire employed.
Aspects of the studies reviewed include basic study
design and population, wording of the questionnaire
regarding nitrite inhalant use, and published results
comparing nitrite use of KS patients with those who
152

Table 1. Epidemiologic studies comparing Kaposi's sarcoma (KS) and opportunistic infections (01)
among gay men with AIDS.

First Year Study Sample size

Author Initiated Population KS OJ Result - Association with KS

Mather-W. 1981 NYC 8 4 Amount of nitrite use

Haverkos 1981 Multisite, US 67 20 Lifetime quantity of nitrite use
Osmond 1983 SF 108 50 Quantity of 'hits' ofnitritesluse
Goedert 1982 BaltINYMC 8 11 Fellatio, enemas, hepatitis B
Polk 1984 4 sites, US 24 35 Lab tests (Hb, T4 count, IgA)
Armenian 1984 4 sites, US 316 510 Composite lifestyle score
Lifson 1984 SF 73 109 Diff. not reported (N02 Neg.)
Messiah 1983 Paris 25 25 Sex, STDs, N02 protective for KS
Archibald 1982 Vancouver 28 61 Sex in SFILAlNY; Nitrite use
Beral 1984 London 30 35 Insertive 'rimming'
Kaldor 1984 Australia 46 88 No significant differences
Page Not stated Several sites 26 85 Higher T4 count

N02 =Nitrites

developed opportunistic infections indicative of AIDS
but not KS. The studies also included questions about
sociodemographics, medical history, use of drugs,
travel, and sexual behaviors. Patients were invited to
provide blood and other specimens for laboratory anal-
ysis. Details about the 12 studies are available in the
published reports referenced after each study.
Results
Twelve studies were identified which met the study
definition. Selected characteristics of the studies are
listed in Table 1. For each study, we describe the basic
study design and population, quote in full the exact
wording of the question(s) used to gather information
on nitrite inhalant use, and summarize the results. The
studies are presented in the same order they are listed
in Table 1. The studies are identified by the institution
or study group of the primary author.
A. Mount Sinai School of Medicine, New York
Study Design and Population: A 4.5 year longitudi-
nal study of gay men with persistent generalized lym-
phadenopathy was started in 1981. Of the 42 partici-
pants, 12 (29%) developed AIDS, eight of whom had
KS. Questionnaires were self-administered.
Questionnaire:
'Poppers'
Have you ever used 'poppers' (inhalants, amyl or butyl
nitrite)? YeslNo
If YES: When did you first use 'poppers'? ---.{year)
When did you last use 'poppers'?
(month/year)
During the period you used 'poppers', how many
months, altogether, did you use them? ---<months)
If we take an average month of use, during how many
days (or nights) would you use them? ----<days and
nights)
If we take an average day (or night) of use, how many
'sniffs' might you take? ----sniffs.
When you use 'poppers', about what percentage of use
is in:
Sexual activity _ _ _%, Disco/Social ___%,
Other __%
Specify
Ofthe 'poppers' that you have used, about what percent
have been:
Ampules ___%, Labelled Bottles ___%,
Unlabelled Bottles ___%'
Results: All 42 men reported nitrite use. The amount
of use was significantly associated with the develop-
ment of KS (Mathur-Wagh et al., 1984; Mathur-Wagh,
Mildvan & Senie, 1985).
B. Reanalysis of CDC Studies-Atlanta, Georgia
Study Design and Population: In 1981 and 1982, the
CDC conducted three separate studies in several large
metropolitan areas of the USA. Of 87 gay men with
AIDS interviewed by CDC personnel, 47 with KS, 20
had Pneumocystis carinii pneumonia (PCP), and 20
had both.
 153

Questionnaire: showed that the variable most strongly associated with

'Have you ever used any type of inhalant sexual stim- KS was the use of larger quantities of nitrite inhalants
ulants or 'poppers' (inhalants, amyl or butyl nitrite) (Haverkos et al., 1985).
before -<onset date)? (CHECK ONE) Yes __
No __ C. University of California at San Francisco
IF YES, ASK: When did you first use 'poppers'? __ Study Design and Population: An AIDS case-control
(year) study among gay men in San Francisco started in 1983
When did you last use 'poppers' before __(onset and evolved into a longitudinal study. By April 1986,
date)? --<year) 158 men in the initial cohort had developed AIDS, 108
During the period that you used 'poppers', how many had KS. Trained interviewers administered the ques-
months, altogether, did you use them? --<months) tionnaires.
If we take an average month of use, during how many
days (or nights) would you use them? --<days and Questionnaire:
nights) 'IF EVER USED POPPERS:
If we take an average day (or night) of use, how many In what year did you first use poppers? _ _year
'sniffs' might you take? -----sniffs. When did you last use poppers? _ _year
When you use 'poppers' about what percentage of use If we take an average month of use, how many days
IS Ill: or nights out of the month would you use them? _ _
Bathhouses _ _ _%, Discos _ _ _%, days
Other (specify) _ _% And on a typical day or night of use, how many hits
Of the 'poppers' that you have used, about what percent would you take? -Ilits'
have been:
Ampules _ _%, Labelled Bottles _ _%, Results: Patients with KS were 2.2 times more likely
Unlabelled Bottles _ _% to report greater than four 'hits' per night than patients
If you use labelled bottles, which brands have you with opportunistic infections. Patients with KS, com-
used? (CHECK IF USED) pared to patients with opportunistic infections, were
more likely to report a large number of sexual partners,
1. Locker Room __ 9. Pig Poppers __ practice analingus, use large quantities of 'recreation-
2. Rush 10. Highball ai' drugs by non-intravenous routes of administration,
3. Bolt 11. Quicksilver __ and receive metronidazole therapy for intestinal para-
4. Hardware 12. Kryptonite __ sites. Patients with opportunistic infections were more
5. Bullet 13. Other (specify) likely to report syphilis and to use drugs intravenous-
6. Disco-Roma ly than were patients with KS. Multivariate analysis
7. Head showed that the variable most strongly associated with
8. Hit KS was the use of more than four 'hits' of nitrites per
night of use (Osmond et al., 1985; Haverkos, 1987).
If you use unlabelled bottles, where do you usually buy
D. National Cancer Institute
them?
Study Design and Population: 285 gay men in Man-
Name of store City hattan or Washington, D.C. were followed starting in
1982. Self-administered questionnaires were given to
participants at entry and at follow up visits. 19 devel-
oped AIDS, 8 of whom had KS.

Results: 84 of the 87 (97 %) reported nitrite inhalant
use. The median cumulative lifetime dose was 384
days. Compared with PCP patients, KS patients and
those with both diseases reported more sexual part-
ners, more 'recreational' drug use, higher incomes, and
higher rates of non-B hepatitis. Multivariate analysis
Questionnaire:
'1. Have you ever used nitrite inhalants ('poppers')?
2. What year did you first start using nitrite inhalants?
3. During the past 30 days, estimate the number of
days you used nitrite inhalants?
Think about the number of days in 1982, 1981, and
1980 when you may have used nitrite inhalants. Fill in
154
the answers for Questions in the chart below for each
year given. (IF ANY ENTRY IS 'NONE', EN1ER '0'
IN THE SPACE).
4. How many days in 1982, 1981, and 1980 did you
use nitrite inhalants? (EN1ER A NUMBER IN THE
SPACE FOR EACH YEAR).
5. On a typical day of use, how many sniffs did you
take? (ENTER A NUMBER IN THE SPACE FOR
EACH YEAR).
6. Did you use any of the following types of nitrites at
least twice a month during every month of that year?
Unlabelled Brown Bottle? YeslNo
Snappers? YeslNo
Brand Name? YeslNo
Which types? (See list below)*
7. Did you use nitrites during sexual acts, at other
times, or both?
(CIRCLE ONE ANSWER). 1. Sex Acts, 2. Other
Times, 3. Both
* Examples of brands are: Rush, Bolt, Locker Room,
Quick Silver, Blackjack, Jac-A-Roma, Heart-On, Bul-
let, Aroma of Men , Toilet Water, Ban Apple Gas, Crypt
Tonight.'
Results: 'Nitrite inhalant use, measured as frequency
during the previous year or intensity (number of sniffs)
during the previous 6 months, was not significantly
associated with AIDS, Kaposi's sarcoma, or Pneumo-
cystis pneumonia.' Several variables were associated
with the development of KS, including receptive fel-
latio, frequent enemas/rectal douches, high levels of
antibody to HBV, and use of methaquaalone (Goedert
et ai., 1987).
E. Multicenter AIDS Cohort Study (MACS)
Study Design and Population: The MACS is a prospec-
tive study of gay men in BaltimorelWashington, Chica-
go, Los Angeles, and Pittsburgh supported by NIH.
4,955 men were enrolled in 1984 and followed every
six months. 1,835 were HIV seropositive on entry, 59
developed AIDS, 24 with KS during a median follow
up of 15 months. Questionnaires were administered by
trained interviewers.
Questionnaire:
'Now let's talk about other drugs you may have used.
As I read each one, please tell whether you used it even
once during the last two years.
'Poppers' like nitrite inhalants (amyl, butyl or iso-
propyl nitrites)?
How about (EACH)? [Have you (taken/used) any
during the last two years?]
How often did you (use/take) (DRUG) during the
last two years?
1. Daily, 2. Weekly, 3. Monthly, 4. Less Often
And how often did you (use/take) (DRUG) during
the last 6 months?
1. Daily, 2. Weekly, 3. Monthly, 4. Less Often
Have you (used it/taken any) within the last 7 days?
YeslNo
IF IN LAST 7 DAYS: How many days ago did you
last use it, or was it today?
I.Toda~2.----Daysago
'Poppers' or nitrites (with sex)
Thinking back over the last two years, was there a time,
even once, when you used drugs while having sex, or
had sex while under the influence of drugs? YeslNo
Now turn to page 4 in your booklet and tell me with
how many partners you used each of the following
drugs during the last 2 years. How about (EACH)?
Proportion of sex partners in last 2 years
1. All, 2. Most, 3. Some, 4. One, 5. None
FOR EACH USED IN LAST 2 YEARS: And dur-
ing the last 6 months, with how many partners did you
use (DRUG) when you had sex? (Instead of using the
booklet page, please give me the approximate num-
ber).'
Results: No association between nitrite inhalant use
and KS was reported. Significant associations for
KS were found for decreased hemoglobin levels,
decreased T-helper lymphocyte counts, and increased
immunoglobulin A levels. The authors state: 'We
asked about nitrite use only within two years of entry
into the study and that we did not attempt to quantify
usage in this analysis. It is thus possible that we have
missed or obscured a meaningful association; future
analyses of quantitative data on nitrite use from our
study should resolve this issue' (Polk et ai., 1987).
MACS (Part 2)
Study Design and Population: As above, An additional
634 men were enrolled in the cohort described above
from April 1987 and September 1991. As of January
1993, 826 men had developed AIDS, 316 with KS.
Baseline interview information was analyzed.
Results: KS patients were most commonly from Los
Angeles; reported greater use of 'recreational' drugs,
in particular poppers and hashish; were more sexually

active by measures of several specific behaviors; and
reported more gonorrhoea, hepatitis, herpes, genital
and anal warts, and scabies. A model combining those
associations (sexual activity, use of nitrites, and sexual
partners from the West Coast) predicted KS. Nitrite use
was reported by 284 of 314 KS patients (90.5%) and
421 of 508 non-KS patients (82.9%) in the 2 years prior
to baseline interview (Odds ratio n = 1.96, Confidence
intervals 1.27-3.04). Use of poppers/nitrites was one of
several variables found to be significant on multivariate
analysis. No quantitative analysis of nitrite use was
conducted (Armenian et al., 1993).
G. San Francisco Hepatitis B Cohort Study-CDC
Study Design and Population: 6,697 gay men in San
Francisco were recruited between 1978 and 1980 for
epidemiologic studies of hepatitis B virus infection. In
October 1983, the San Francisco Department of Public
Health and the CDC began to examine the occurrence
of AIDS among members of the cohort. A sample of
men from the original cohort was contacted, asked
for consent to test current and stored samples for HIV
antibody, examined by a physician and interviewed.
Men who subsequently were reported with AIDS to the
San Francisco and national AIDS surveillance systems
were studied.
Interview data were available for 182 men with
AIDS, 73 with KS.
Questionnaire:
'DRUGS AND SUBSTANCES: The next part of this
study concerns the use of certain drugs. The first few
questions are about drugs you might have smoked,
sniffed or swallowed. Later I'll ask a few questions
about drugs and substances that can be injected. Before
_ (ONSET DATE FOR AIDS) or in the past _
months, about how many days in an average month
would you use ... (NOTE: If never code 00, if less
than once a month, code 01
Recreational drug
or substance Days/Month Comment
Nitrite Inhalants:
Unlabeled bottles
Nitrite Inhalants:
Labelled bottles
Nitrite Inhalants:
Ampules
Results: Men with KS did not differ from men with
opportunistic infections with respect to number of
sexual partners, history of sexual or enteric diseases,
155
use of 'recreational' drugs, including nitrites, or par-
ticipation in specific sexual acts (Darrow et al., 1987;
Lifson et al., 1990).
1nstitut National de la Sante et de la Recherche Medi-
cale, France
Study Design and Population: Hospitalized AIDS
patients in the Paris metropolitan area were recruit-
ed between May 1983 and July 1984 and interviewed.
25 gay men with KS and 25 gay men with opportunistic
infections were interviewed by one of the authors.
Questionnaire:
'RESEIGNEMENTS SUR LA PRISE EVENTUELLE
DETOXIQUES
Avez-vous deja utilise des stimulants per inhalation,
de type poppers?
OUI NON
Si OUI, indiquez avec quelle frequence et a quelle
epoque vous les avez utilises:
Nombrede Periode
fois/mois Debut Fin
mois annee mois annee '
Translation: QUESTIONS ON THE USE OF TOXIC
DRUGS .... Have you ever used inhalant stimulants,
such as poppers? YESINO. If YES, indicate.the fre-
quency and timing of their use. Number of times per
month; period use begun and ended, month and year.
Results: Nitrite use was reported by 16 of the 25 KS
patients and 23 of the 25 patients with opportunis-
tic infections. Patients with opportunistic infections
reported more syphilis, gonorrhoea, nitrite inhalations,
and more sexual partners than patients with KS (Mes-
siah et al., 1989).
1. University of British Columbia, Vancouver
Study Design and Population: The Vancouver
Lymphadenopathy-AIDS Study is a prospective study
of gay men recruited from six general practices in Van-
couver between 1982 and 1984.353 HIV seropositive
men were followed. 99 of the men developed AIDS by
October 1990, 28 had KS. A self-administered ques-
156
tionnaire was completed as part of regularly scheduled
visits with their clinician. Enrollment questionnaires
were analyzed.
Questionnaire:
'Inhalants
Have you ever used any type of inhalant, sexual
stimulant-poppers (amyl or butyl nitrite)?
---No/never ------Stopped (When? 19 __)
Yes
If YES or STOPPED, when did you first use? 19__
When did you last use? -Less than 1 week ago
__Over 1 week but less than 1 month ago
__Over 1 month but less than 6 months ago
__Over 6 months ago
For how many months altogether have you been
using/used poppers? ------Il1onths
In a typical day/night of use, how many 'sniffs' would
you take? -----sniffs
Of the poppers that you have used, estimate the amount
that have been ...
Ampules: none, rarely, occasionally, often, usually,
always
Labelled bottles: none, rarely, occasionally, often, usu-
ally, always
Unlabelled bottles: none, rarely, occasionally, often,
usually, always
Solids: none, rarely, occasionally, often, usually,
always
For LABELLED BOTILES, which brand(s) do/did
you usually buy?
(0 = none, 1 = rarely, 2 = occasionally, 3 = often,
4 = usually, 5 = always) Locker Room __ , Bolt _
_ , Rush __ , Hardware __ , Bullet __ , Disco
Roma __ , Head __ , Hit __ , Highball __ ,
Pig Popper __ , Quicksilver __ , Kryptonite _ ,
Other (specify) _ __
For unlabelled bottles, where did you usually buy
them?
_ _ _Name of store, _ _ _Name of city'
Results: On logistic regression, two variables were
related to Kaposi's sarcoma-high numbers of sexual
contacts during 1978-1982 in San Francisco, Los
Angeles, and/or New York (Relative risk = 3.5), and
greater than 20 'hits' of nitrites in the month prior to
interview (Relative risk = 2.3) (Archibald et al., 1990,
1992).
J. Imperial Cancer Research Fund, Oxford, UK
Study Design and Population: 65 gay men with AIDS
were entered into a KS case comparison study. 45 of
the men were recruited and interviewed before they
developed AIDS. These 45 were part of a cohort of
asymptomatic sexual partners of men with AIDS, had
lymphadenopathy, or were otherwise regarded as at
risk for AIDS. Recruitment began in 1982 and inter-
views were conducted between May 1984 and Febru-
ary 1985. The other 20 men were recruited shortly after
their AIDS diagnosis at Middlesex Hospital. 30 of the
men had KS, 35 had other AIDS-defining illnesses.
The questionnaires were administered by physicians.
Questionnaire:
'Have you ever used the following?
Lifetime How often during the previous 5 years
experience
No. years Never <lImth IImth =lIwk >lIwk
used
Amyl or
butyl
nitrite
Have you ever injected any of these drugs?'
Results: KS was more common in the most sexual-
ly active men. Insertive 'rimming' was significantly
associated with KS. 59 of the 65 men reported nitrite
use; however, use of nitrites was not associated with
KS (Beral et al., 1990, 1992).
K. Sydney AIDS Prospective Study, Australia
Study Design and Population: Within a cohort study
started in 1984, 46 men who developed KS were com-
pared to 88 men with AIDS but not KS.
Questionnaires were self-administered.
Questionnaire:
'During the past 3 months have you used any of the
following drugs? If yes, please write in the average
number of times per month.
Nitrite inhalants

Results: No significant differences emerged (Kaldor et
ai., 1993).
L. Tricontinentai Seroconverter Study Group
Study Design and Population: The Tricontinental Sero-
converter Study is an international collaboration which
combines data from 5 cohorts of gay men from Ams-
terdam, Berkeley, New South Wales, San Francisco,
and Vancouver. Of 403 men observed through Octo-
ber 1992, 26 had developed KS as their only AIDS
defining illness. These 26 were compared with 85 with
AIDS but not KS. How interviews were conducted was
not stated, but presumably varied by study center.
Questionnaire: Each study center used its own ques-
tionnaire (see C, E, I, K).
Results: CD4 counts were higher at diagnosis for KS
patients (mean 150 cells per microliter for patients with
KS, 120 cells per microliter for those with 01). No
differences were noted for sexual behaviors. Nitrite
data were not mentioned in the abstract (Page et ai.,
1993).
Discussion
The questions used to ascertain and measure nitrite
exposure vary widely from study to study. Investiga-
tors are encouraged to develop and use standardized
questions to ascertain and quantitate nitrite exposure
in epidemiologic studies. The concept of 'pack-years'
to quantitate tobacco use may serve as a model.
The results of this review of epidemiologic stud-
ies and the development of KS among gay men with
AIDS are inconclusive. Two variables, namely risky
sexual behaviors and nitrite inhalant use, are repeated-
ly associated with diagnosis of KS. Of the 12 studies,
four find a strong association between large quantities
of nitrite use and KS (ABCI), six find no association
(DEGJKL), one finds a weak association (F), and one
finds nitrites protective for KS (H).
We reviewed the questions addressing sexual
behavior for most of these studies and note that the
content of sexual questions is more similar than drug
use history questions. It is our belief that the identi-
fication of a retrovirus as the cause of AIDS in 1983
and 1984 led to significant changes in the content of
the questionnaires. After HIV was found, behavioral
questionnaires focused even more emphasis on modes
157
of sexual transmission and less attention on drug use,
particularly nitrite inhalant use.
The differences in outcomes of these studies may
reflect the differences in study designs, sample sizes,
timing, quality, and content of interviews, and lab-
oratory studies (Haverkos & Drotman, 1991; Turner
et ai., 1992; Turner, Lessler & Devore, 1992). Epi-
demiologic study with careful consideration to con-
tent of questionnaires and laboratory testing may yet
reveal the causes or co factors for this tumor. The cur-
rent epidemic of AIDS-related KS provides a unique
opportunity to decipher the pathogenesis of a malig-
nancy which is multifactorial in etiology (Drotman &
Haverkos, 1992).
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Archibald, c.P. et aI., 1990. Risk factors for Kaposi's sarcoma in the
Vancouver Lymphadenopathy-AIDS study. J. AIDS 3 (Suppl. 1):
SI8-S23.
Archibald, c.P. et aI., 1992. Evidence for a sexually transmitted
cofactor for AIDS-related Kaposi's sarcoma in a cohort of homo-
sexual men. Epidemiology 3: 201-209.
Armenian, H.K. et al., 1993. Composite risk score for Kaposi's
sarcoma based on a case-control and longitudinal study in the
Multicenter AIDS Cohort Study (MACS) population. Am. J. Epi-
demiology 138: 256-265.
Beral, V. et al., 1990. Kaposi's sarcoma among patients with AIDS:
A sexually transmitted infection? Lancet 335: 123.
Beral, V. et aI., 1992. Risk of Kaposi's sarcoma and sexual practices
associated with faecal contact in homosexual or bisexual men
with AIDS. Lancet 339: 632-635.
Darrow, W.W et al., 1987. Risk factors for human immunodeficiency
virus infections in homosexual men. Am. J. Public Health 7: 479-
483.
Drotman, D.P. & H.W. Haverkos, 1992. What causes Kaposi's sar-
coma? Inquiring epidemiologists want to know. Epidemiology 3:
191-193.
Goedert, U. et aI., 1987. Effect of T4 count and cofactors on inci-
dence of AIDS in homosexual men infected with human immun-
odeficiency virus. JAMA 257: 331-334.
Haverkos, H.W., 1987. Factors associated with the pathogenesis of
AIDS. J. Infect. Dis. 156: 251-257.
Haverkos, H.W. & D.P. Drotman, 1991. Kaposi's sarcoma in a cohort
of homosexual and bisexual men: Epidemiology and analysis for
cofactors (letter). Am. J. Epidemiol. 133: 514-515.
Haverkos, H.W., D.P. Drotman & D. Hanson, 1993. Epidemiology
of AIDS-related Kaposi's sarcoma (KS): An update. IXth Inter-
national Conference on AIDS, Berlin, Germany, PO-BI2-1576;
1: 398.
Haverkos, H.W., D.P. Drotman & WM. Morgan, 1990. Kaposi's
sarcoma in patients with AIDS: Sex, transmission mode, and
race. Biomed. & Pharmacother. 44: 461-466.
Haverkos, H.W. et aI., 1985. Disease manifestation among homosex-
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men with acquired immunodeficiency syndrome: A possible
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Lifson, A.R. et al., 1990. Kaposi's sarcoma in a cohort of homosexual
and bisexual men: Epidemiology and analysis for cofactors. Am.
J. Epidemiol. 131: 221-231.
Mathur-Wagh, U. et al., 1984. Longitudinal study of persistent
generalized lymphadenopathy in homosexual men: Relation to
acquired immunodeficiency syndrome: Lancet 1: 1033-1038.
Mathur-Wagh, U., D. Mildvan & R.T. Senie, 1985. Follow-up at 4!
years on homosexual men with generalized lymphadenopathy. N.
Engl. J. Med. 313: 1542-1543.
Messiah, A. et aI., 1989. Possible correlation between exposure to
AIDS risk factors, clinical presentation in AIDS, and subsequent
prognosis. Eur. J. Epidemiol. 5: 336-342.
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Immunodeficiency Syndrome (AIDS), Atlanta, Georgia.
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Polk, B.P. et al., 1987. Predictors of the acquired immunodeficiency
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Turner, c.P., J.T. Lessler & Devore, 1992. Effects of mode of
administration and wording on reporting of drug use. In: Survey
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© 1996 Kluwer Academic Publishers.
A hypothetical disease of the immune system that may bear some relation to
the Acquired Immune Deficiency Syndrome
Kary B. Mullis
6767 Neptune Place, Apt. 5, La Jolla, CA 92037, USA
Received 12 Apri11994 Accepted 14 June 1994
Abstract
The cells of an individual immune system could be so highly infected with latent viruses that were immunologically
distinct from one another as to result in an immune dysfunction resembling the Acquired Immune Deficiency
Syndrome.
There is a population of cells in a particular individual
from which sub-populations are chosen by immune
mechanisms to undergo clonal expansion in the course
of normal immune function. The number of individual
cells in such a sub-population in any particular episode
of immune function is dependent on a variety of factors
that are incompletely understood.
1. Call this number of cells R.
2. Assume that in this population of cells at least one
cell in R is latently infected by at least one virus
capable of expressing a new and distinct epitope.
3. Now, every episode of immune function involving
the promotion to clonality of R cells will result in
the clonal expansion of at least one latently infected
cell.
4. And during the course of clonal expansion the like-
lihood for expression of a latent virus from one or
more members of the growing infected clone would
be expected to grow in proportion to the number of
cells in the clone.
5. Because expression of a previously latent virus
with a distinct epitope would tend to provoke a
new immune response, every immune response
would tend to provoke at least one further immune
response.
6. AIDS may be the result of such a chain reaction.
The immune system so infected would be perpetu-
ally generating new immunogens. As the frequency
of infection increased such an immune chain reaction
would be progressively more debilitating for the sta-
bilityand effectiveness of immune function. At a level
of infection where more than one latent viral species
159
existed in R cells, a single immune response on aver-
age would result in the release of more than one new
viremia. Such a situation would generate an exponen-
tially increasing number of independent immune stim-
uli and, unless somehow controlled, would certainly
be fatal.
It is difficult to imagine a control mechanism that
would not seriously compromise immune function.
Mechanisms for such control may not have evolved
because selection pressures for the evolution of such
mechanisms would only have existed if there were a
sufficient diversity of viruses available in the environ-
ment capable of latently infecting mammalian immune
cells to a level near lIR.
However, in the past century humans have come to
constitute a greater and greater proportion of their own
environment, and therefore the availability of diverse
and infectious human viruses may have risen signifi-
cantly. Certainly the increase in speed of transportation
has dramatically increased the number of other human
beings anyone individual will encounter during the
course of a lifetime.
Certain life styles have been in the vanguard of this
development. For instance, it has been widely pub-
licized that in the so-called "bath house cultures" of
some metropolitan gay communities, intimate expo-
sure to hundreds of individuals per year was unexcep-
tional until very recently when viral infection became a
serious issue. The potential 'for collecting a vast num-
ber of diverse latent viruses through intimate expo-
sure to hundreds of different human beings per year is
increased enormously if those humans are also being
160
exposed to hundreds of different humans per year. Thus
300 contacts with people having themselves 300 con-
tacts at a first approximation yields an exposure level
90,000-fold higher than that incurred by contact with a
stably pair-bonded individual. Going out in the spread-
ing pyramid of exposure one step further generates a
relative risk factor of 27 million. The particular social
dynamic of the metropolitan, international, gay, bath
house community could not have been more efficient-
ly organized if maximum exposure by individuals to
the world's supply of diverse viruses had been actively
sought.
Other modes for unprecedented accumulation of
diverse viral infections can be envisioned. Transfusion
of blood from one or more highly infected individuals
could transfer a sufficiently large number of viruses
to cause immune dysfunction. Or long term associa-
tion with an individual harboring a sufficient number
of diverse viruses as to be suffering from immune dys-
function could transfer a sufficient number of them to
an otherwise unexposed individual. It would not be
expected that a casual or brief encounter with such an
infected individual would be sufficient to transfer a
lethal diversity of viruses. At a given time most viral
infections in an individual are latent.
For the purposes of this hypothesis, the absolute
levels of infection are not critical. Social and tech-
nological developments in this century have raised
the potential for multiple modes of accelerated trans-
mission for infectious organisms and this has resulted
in the catastrophic accumulation of an evolutionari-
ly unprecedented burden of latent infections in some
humans. This is all that the present hypothesis assumes.
If this mechanism is causal for AIDS, then the pres-
ence of any particular virus would not be necessary or
sufficient for the development of that disease, although
someone so afflicted might be expected to have a far
greater than average chance of being infected by any
particular virus, for instance HIV, than someone not
afflicted.
This hypothesis is not inconsistent with the notion
that one or more species of virus may be dispropor-
tionately effective in achieving a highly diverse state
of immune cell infection. Some viruses, for example,
might be far more effective than others at spreading
significantly mutated copies of themselves throughout
the population and throughout the immune system of
an infected individual. The high rate of mutation in
the Retroviridae and their capacity for latent infection
make them ideal candidates for such a role. HIV might
be a significant species, but absent any evidence for
this there is no reason to suspect it over any other
virus, most of which, it can be easily argued, are not
presently detectable.
Such a mechanism would predict that any drug that
could prevent the growth of latent viruses would be
beneficial, unless of course it were poisonous to the
patient. However, unless latent chromosomally incor-
porated viruses could somehow be removed or per-
manently prevented from expressing new epitopes, no
cure would be expected.
This hypothesis predicts that a vaccine against any
specific virus would be ineffective against AIDS.
This hypothesis is consistent with a disease of
slow onset with a steadily more rapid progression.
Progression of the disease would be accelerated by
any immune activity whether it be elicited by infec-
tion, environmental immunogens, immune reactions
to drugs, etc. Progression of such a disease would
also be enhanced by the rapid growth of any infected
cells that were capable of producing infective viruses,
particularly if these infective viruses were capable of
infecting immune cells.
Usefully, this hypothesis is subject to experimental
verification or denial. If correct, then an experimental
animal model of AIDS should be induced in labora-
tory animals by infecting them at a low mUltiplici-
ty with a very large number of diverse viruses. One
way of doing this would involve collecting the blood
from a large number of wild mice from geographical-
ly distant locations, mixing it together and injecting it
into healthy mice. The number of mice that would be
required to produce such a lethal injection or series of
injections is not predicted by this hypothesis, although
from the numbers suggested by the behavior patterns of
the human victims of AIDS the number of individuals
whose viruses must be pooled could be quite high.
The hypothesis suggests that some level of diverse
infection would cause AIDS-like malfunction of the
immune system to appear rapidly, and that this could
not be reproduced by simply isolating a particular
infectious species and infecting similar animals with
only this species.
The hypothesis also suggests that blood from a sin-
gle human AIDS patient should be capable of trans-
ferring the appropriate level of diversity of infection
to another organism, given that the recipient organism
contains a functional human immune system.
The hypothesis suggests further that aliquots of an
appropriate dilution of the blood from a single AIDS
patient injected into a large number of experimental
animals with a human immune system would not be
 161

able to produce AIDS-like immune dysfunction in any Acknowledgements

one of them.
According to this hypothesis there is not a single The author is grateful for more than a little help from
organism that is the cause of AIDS, and there should Stephen H. Judd and Andrew E. Dizon in clarifying
exist AIDS patients who do not test positive for HIY. his thoughts and rendering his prose more intelligible.
It is an overwhelming number of distinct organisms
which causes the immune dysfunction. These may
individually be harmless.
P. H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 163-183, 1996. 163
© 1996 Kluwer Academic Publishers.

The epidemiology and transmission of AIDS: a hypothesis linking

behavioural and biological determinants to time, person and place

Gordon T. Stewart
Emeritus Professor of Public Health, University of Glasgow, Glasgow G12 8QQ, UK
Present address: Glenavon, Clifton Down, Bristol BS8 3HT, UK

Received 12 January 1994 Accepted 14 June 1994

Abstract

Epidemiologically, the Acquired Immune Deficiency Syndrome, AIDS, is transmitted and distributed in the USA
and Europe almost entirely in well-defined subsets of populations engaging in, or subjected to, the effects of
behaviours which carry high risks of genital and systemic infections. The persons predominantly affected are those
engaging in promiscuous homosexual and bisexual activity, regular use of addictive drugs, and their sexual and
recreational partners. In such persons and in subsets of populations with corresponding life-styles, the risk of AIDS
increases by orders of magnitude. Because of continuity of risk behaviour and of associated indicator infections,
the incidence of AIDS over 3-5 year periods is predictable to within 10% of actual totals of registered cases in
the USA and UK. Secondary transmission of AIDS beyond these groups is minimal or, in many locations, absent.
There is no indication of appreciable spread by heterosexual transmission to the general population.
The Human Immunodeficiency Virus, HIV, is transmissible to some extent in general populations, and more
so among promiscuous persons. It may cause viraemia, lymphadenopathy and latent infection (HIV disease) in
anyone. In persons engaging in risk behaviours which themselves alter or suppress immune responses, it can interact
with MHC, antibodies to other organisms and to semen, and other allogenic antigens to initiate a programmed
death of CD41ymphocytes and other defensive cells, as in graft-host rejections. This occurs also in haemophiliacs
receiving transfusions of blood products, and is more pronounced in persons with reactive HLA haplotypes. The
susceptibility of particular subsets of populations to AIDS is thereby largely explained. But these changes occur
in the absence of HIV, and so do Kaposi's sarcoma, lymphadenopathies and opportunistic infections which are
regarded as main indicators of AIDS. The hypothesis that HIV-l can do all this by itself and thereby cause AIDS
is falsifiable on biological as well as epidemiological grounds.
An alternative hypothesis is proposed, linking the incidence of AIDS to the evolution of contemporary risk
behaviour in particular communities and locations in the USA, UK and probably in most of Europe. It does not
pretend to explain the reported incidence of AIDS in Africa and other developing regions where data are insufficient
to provide validation of the pattern of disease and contributory variables.
The immediate, practical implication of this alternative hypothesis is that existing programmes for the control of
AIDS are wrongly orientated, extremely wasteful of effort and expenditure, and in some respects harmful.

Introduction wide consensus in medical science and beyond that

In 1984, a US Secretary of State announced that a retro-
virus then named HTLV3, isolated from one patient
in Paris, was the unique cause of loss of immunity
in a severe infectious disorder first described in 1981
in some homosexual men and drug addicts admitted
with unusual symptoms to hospital in New York City
and California. Since then, there has been a world-
this retrovirus, renamed HIV-l, and its innumerable
variants are the unique cause of a more complex and
extending range of disorders classified and repeatedly
re-classfied as the Acquired Immune Deficiency Syn-
drome, AIDS. When this consensus was challenged by
PH. Duesberg in 1987 (see below), R.C. Gallo, the
chief proponent of the claim for HTLV3, and lead-
ers of the consensus replied in a Forum reported by
164

Table 1. Predictions of new cases and cumulative totals of AIDS in 1991 and 1992 in England
and Wales by different methods.

Mathematical methods Predictions for years:

with references(a-d) 1991 1992 1982-92
High predictions(a)
Exponential 6240 10700 24640
Wilkie: actuarial 6380 9152 24341
Day: Weibull 5160 8080 20582
Center for Disease Control 6273 10308 25618
Healy: extrapolation 8474 15440 34077
Middle of the range(a)
US growth model 3950 4800 16270
Wilkie: actuarial 3067 3770 13361
Anderson" 3030-3940 3810-4950 12010-15190
Cox: model for planning 2950 3600 12750
Royal Society Symposium, 1989(b)
Day et al: back projection 737-3538 5101-12103
Wilkie: actuarial 3490-12097 13000-27000
Ishan: various 2272-2420 10950-11794
Low predictions:
Public Health Lab Service, 1990 1090-2400
Stewart: regression""( c,d) 1254 1457 6101
Total of registered cases 1275 1418 6929

(a) See reference: Dept. of Health and the Welsh Office, 1988.
(b) See reference: Cox DR, Anderson RM, Hillier HC (eds). Phil Trans R Soc London (B)
1989; 325; 37-187.
(c)See reference: Stewart GT. Soc of Public Health, Official Handbook 1992-93.
(d) See reference: Lancet, 1993; 341; 898.
"From a model of transmission in homosexual men, proportionally adjusted to allow for
heterosexual transmission.
"" Rolling average, incidence/time; coefficient of correlation, r > 0.9.

Science Magazine (1988;241 ;514) that the 'Strongest
evidence that HIV causes AIDS' came less from iso-
lates of the virus itself than from prospective epidemi-
ology. Having been engaged in epidemiological work
which suggests the reverse, I then began a long struggle
to persuade the immense epidemiological sector of the
consensus that this assertion, no less than the microbio-
logical evidence of causation of AIDS by HIV, merited
reconsideration.
When Duesberg challenged the HIV hypothesis in
1987, the epidemiological evidence depended essen-
tially upon a correlation between antibodies to HIV
and a diagnosis of AIDS. This was a circular argument
since, after 1984, sero-positivity to HIV mandated a
diagnosis of AIDS in patients with a scheduled range
of diseases, whether or not they were in risk groups.
In 1989, a formidable defence of the epidemiologi-
cal consensus was presented by the Royal Society of
London in a Symposium (Cox, Anderson & Hillier,
1989) of invited papers which analysed the epidemic
of AIDS to date in the UK and made predictions about
its incidence through 1992. These analyses and pre-
dictions, like those of a preceding official Report (UK
Dept. of Health and the Welsh Office, 1988), rested
upon assumptions not only that HIV was the essential
cause of AIDS in all its forms but also that all who
were sero-positive would get AIDS which would then
cause epidemics of tens of thousands of cases by het-
erosexual transmission in the general population of the
UK.
The assumption that HIV would spread by hetero-
sexual transmission was, to a limited extent, correct but
predictions of similar spread of AIDS, as in the Lon-
don Declaration of 1988, from the WHO (Mann, 1989;
Sato, Chin & Mann, 1989) and by the Advisory Com-
mittee on Dangerous Pathogens (1990) were numeri-
cally exaggerated (Table 1), as were actuarial and other
projections used for planning and estimates of spread
 165

Table 2. Cumulative total of registered cases of AIDS in the United Kingdom (UK) and New York City (NYC) from 1982 to April 1994.

UK NYC
Presumed mode of population 57,000,000 population 7,324,711
transmission male female male female

Sexual intercourse
between males 6735 (86% of 7813) 23869 (50% of 47299)
do plus IDU' 144 1926
between male and female*' 587 446 (5 % of 8407) 203 3254 (6% of 57769)
do high risk 28 82 nla nla
do abroad 503 324 nla nla
do within UK 56 40 nla

Injecting drug users' 347 148 21301 7216

Subtotals 7813 (93%) 594 (7%) 47299 (82%) 10470 (18%)

Totals 8407 57769

Mother to infant'" 61 66 1246

Blood or transplant 435 69 214 101
Undetermined lOS 18 3267 1287

Subtotals 8414 747

Totals (incidence of 9161 (1.6) 63884 (87.2)

AIDSllO,OOO population)

• Injecting drug users.

"Includes injecting drug users as sexual partners.
"'Including twins. Of 1198 mothers, 1170 (98%) were in high risk groups, 28 (2%) unknown.
nla: Information not available after 1992 because of revision of CDCIWHO classification; see text.
Sources of data: UK: AIDSIHIV surveillance (Public Health Laboratory Service).
NYC: AIDS surveillance updates. (City Health Dept.).

1_ Predicted Y

L_ • _ _ y =No of new cases (registrations)

3 4 5 6 7 8 9 10 11 12
=
x time units (years)

Fig. 1. New cases of AIDS in New York City, 1982-93.

 166

y= 900

800
y registration data 845. prediction 802 (739-849)
700

600
I - Registrations
500
! ---- Prediction

400

300

200

100

o
1984 1985 1986 1987 1988 1989 1990 1991 1992 1993

x=units of time
Fig. 2. AIDS in the UK: trend 1989-93 from regression y/x 1983-88.

outside the original risk groups of homosexual men and
drug addicts. They were particularly wrong (Table 2) in
the prediction that heterosexual transmission of AIDS
in the general population would give rise to a gener-
al epidemic (Anderson & May, 1987; Public Health
Laboratory Service, 1990). What the epidemiological
evidence did show in the USA, in the UK, and most of
Europe and Australasia, was a continuing increase of
AIDS in the original high risk groups. This trend is so
consistent that, even in New York City, an original epi-
centre of AIDS, a regression model (Stewart, 1992a,
1993a) of incidence over units of time since 1983 pre-
dicted in 1989 a cumulative total of 45,487 cases by
=
the end of 1992 (N 44,231). Predictions for the inter-
vening years were correct to within 10% of registered
cases though, in 1993, there was a departure from lin-
earity caused entirely by reclassification of AIDS by
the CDC in that year (see below) to include all cases of
carcinoma of the cervix, tuberculosis and many bacte-
rial pneumonias in HIV-seropositive patients (Fig. 1).
In the UK, with a much lower incidence, regression
models through 1993 and to date are equally accurate
(Fig. 2). AIDS is a disease which began and spread in
males. In females and their infants outside risk groups,
the incidence of AIDS after ten years is negligible in
the UK as in New York City (Table 2).
All of this is verifiable in the registrations pub-
lished by official surveillance in the USA and UK.
The epidemiological evidence in New York City does,
however, indicate an increase of AIDS by presumed
heterosexual transmission in men and women in the
black-Hispanic ethnic minorities in parts of Manhat-
tan, Brooklyn and Queens, especially if they use drugs
(Stoneburner et al., 1990). To investigate the role of
HIV in this, Pagano et al. (1991) used an elaborate
model with three levels of sero-prevalence to estimate
the incidence of AIDS through 1995. Their estimates
for 1991 ranged from 16,106 assuming no new infec-
tions to 29,962 assuming 10,000 new infections annu-
ally (N = 6,800). Fordyce et ai. (1991) estimated the
cumulative incidence of AIDS in female partners of
drug addicts to be 3,900 (N = 4091) from formulae
based on conditional probabilities of uninfected wom-
en acquiring HIV from infected male partners. But if

P/ivdu, the probability that a woman in New York will
have a drug user as a sex partner, is replaced in the
model by the alternative probability P/hiv that she is
equally or more likely to be infected by any man who
is HIV-positive, the estimate of AIDS again becomes
exaggerated.
Incidence in the UK expressed as a rolling aver-
age or periodically since 1982 (Stewart, op. cit.) -
and despite considerable fluctuations in reporting -
follows the same close correlation with units of time
(r =0.97). Regression accurately predicted about 3,000
cases by December 1989 (N = 2,830), 1,254 in 1991
(N = 1,275), 1,365 in 1992 (N = 1,418) and in cumu-
lative total, excluding visitors, of 6,540 (N = 6,929,
including visitors) by the end of 1992 (Tables 1 and 2,
Fig. 2). This is very much less than the range of 3,810
- 4,950 predicted by Anderson (2) for the year 1992
which gave a cumulative total, for planning, of 12,010
- 15,190 cases in the UK by December 1992 and much
higher totals thereafter. In contrast, the regression mod-
el predicted only 1,554 new cases (excluding visitors)
in 1993 when the actual total (including visitors) was
1,619, to give a cumulative total by 1994 of 8483 cas-
es (N = 8529), over 3,000 less than the lowest official
estimate for 1992.
The large errors in these predictions in Britain and
in the USA are inherent. They derive from acceptance
of the hypothesis that continuing sexual transmission
of HIV is the main determinant of the incidence of
AIDS. This led to further assumptions that heterosexu-
al transmission will increase until females are equally
at risk, that all who are infected with HIV will develop
AIDS sooner or later and die, and that mathematical
models based on this reasoning will predict the course
of events correctly, within wide limits. The passage of
time and the data since 1989 in the USA and in Britain
falsify all this (Tables 1 and 2).
So also do back-projections for the UK, projec-
tions by Bregman and Langmuir (1990), based on
Farr's Law of Epidemics, for the USA and estimates
using socio-geographic data in New York City (Wal-
lace, 1991). But predictions based on regression equa-
tions (Figs. 1 and 2) are more reliable because they
leave less than 10% of residual variance in incidence
since 1983 unexplained. Such accuracy in a determin-
istic model is highly unusual. The most obvious reason
is that transmission and expression of AIDS is restrict-
ed to subsets of the popUlation which engage in, or are
exposed to, the effects of continuing risk-behaviour
(Stewart, 1990a, 1991, 1992a). Even in those subsets,
the incidence may now be decreasing in the USA and
167
the UK. The accuracy of predictions from raw data by
regression methods is consistent with the finding that,
while HIV-l has already spread widely in both sexes
because of its presence in genital secretions and in nee-
dles shared by drug addicts, the occurrence of AIDS
beyond risk groups, as predicted in all official surveys,
is low or absent even in communities where HIV-l is
prevalent. The differences in levels of risk, calculat-
ed from best estimates of relevant denominators, are
enormous (Table 3) and need much more attention.
The obvious conclusion is that, in such com-
munities, AIDS cannot develop unless other inter-
acting causes of immuno-suppression and cachexia are
present. Registration data from the USA since 1985
show that prevalence of HIV and AIDS is strongly
influenced by ethnic, urban, economic, social, occu-
pational and mobility factors. In New York City, the
situation is dominated by the fact that 60% of adults
and 90% of infants with AIDS are in Black or Hispanic
communities and by the 33-fold difference in rates of
disease, from <50 to > 1,500 per 10,000 adults, in dif-
ferent districts of the city (Table 2). In the UK, analyt-
ical data are much less precise but, to 30th June 1992,
1,354 cases of AIDS (38% of the cumulative total for
Britain) were reported from NW London; 94% ofthese
cases were male and 91 % ofthem homosexual. Despite
this prevalence of AIDS and also of HIV seropositivity,
at least 20 times higher than the remainder of Britain,
there were only 31 cases of AIDS in women transmit-
ted by (presumed) heterosexual intercourse out of 401
who were seropositive. Infants born in London in 1992
were much more often seropositive than those born out-
side but, because surveillance is voluntary, unlinked,
anonymous and confidential, it is impossible to know
how this relates to the risks, status and treatment of
the 50 mothers who have given birth from 1982-93 to
babies who developed AIDS (about 1: 120,000 births).
In southeast England generally, it was estimated that
92% of neonatal seropositives and 7 out of 8 babies
who developed AIDS in the first year of life came
from mothers who were born in Africa (Ades, Parker
& Cubitt, 1992). There is clearly a pressing need for
a more informative data base and correlation matrix
in the UK but, even in these limited data, it would
appear that there is no appreciable spread of AIDS to
infants from their mothers in the general population
outside specified risk groups in or from well-defined
locations.
168

Table. 3. Cumulative prevalence per 1000 and distribution of AIDS in the UK by main risk groups.

Group Population AIDS in 1990 AIDS in 1994 Relative risk,

(estimates, in No Prev No Prev Group/uK dolLR
thousands) 1994 data·

UK entire population 57,000 3845 0.06 9161 0.16 1.0

UK 15-65 yrs Males 15,000 3234 0.2 7682 0.5 3.1
UK do Females 15,000 207 0.007 597 0.04 0.25
UK homlbisex Males 840 3234 3.9 6879 8.2 51.3 2733
Central London, do·· 50 2265 45.3 3577 71.5 469 24000
UK drug users (200) 222 1.1 495 1.2 7.5 400
UK Heterosex M+F 33,000 268 0.008 1049 0.03 0.19 10
UK do ... Low risk· 33,000 26 0.0008 98 0.003 0.019 0.12

·Ratio of prevalence in Group to that of entire population of UK, and to Low Risk Group (LR) ie =
heterosexuals with no known contact with high risk groups.
··50-70% ofthis risk group are registered in two postal districts of central London

The current hypothesis cumb to a specific syndrome of generalised immune

The hypothesis that HIV is the unique cause of AIDS
is an inductive generalisation based on a few agreed
facts and an acceptance in medical, sociological and
political circles of corroborative reasoning, conjecture
and consensus. The facts (Barre-Sinoussi, Chermann
& Rey, 1983; Gallo, Salahuddin & Popvic, 1984; Dal-
gleish et aI., 1984; Levy & Chimabukuro 1985; Ho,
Pomerantz & Kaplan, 1987; Hanafusa, Pinter & Pull-
man, 1987; Gallo, 1987) are that (i) HIVs can be isolat-
ed from, or identified by biochemical probes in cells,
blood and secretion of an (unknown) proportion of
patients with AIDS; (ii) in patients with AIDS who
are tested serologically, antibodies specific for anti-
gens prepared from envelopes of the original isolates
ofLAVIIH1LV III are usually detectable; (iii) in terms
of this test, there is a correlation between the presence
of HIV and AIDS in a community; (iv) HIVs appear
to be transmitted from person-to-person by anal and
vaginal intercourse, or parenterally via infected nee-
dles or blood transfusion, or congenitally; and (v)
HIVs have high affinity for, and fuse with specif-
ic CD4 membrane receptors on helper T-Iymphocytes
and other mononuclear cells, transcribe their RNA into
the DNA of the cells' nuclei and form virions which
can infect other T-Iymphocytes. The reasoning (Ho,
Pomerantz & Kaplan, 1987; Blattner, Gallo & Tenin,
1988; Institute of Medicine, 1988; Baltimore & Fein-
berg, 1989; Fauci, 1988) is that HIVs can thereby
weaken or destroy cell-mediated immunity, and that
persons thus affected always or almost always suc-
deficiency which then renders them susceptible to oth-
er, opportunistic infections and to various disorders of
lymphoid cells and vital processes with fatal or near-
fatal results. The conjecture of these authors and very
many others is that infection with HIV is necessary and
sufficient to explain this pathogenesis, irrespective of
risk-behaviour. The consensus of the medical and sci-
entific establishment, and practically all health author-
ities is that epidemiological evidence and predictions
support this reasoning, and that any departure from it
is heresy, a threat to public safety and efforts to control
a dangerous epidemic, and to dedicated research.
Weakness in the HIV hypothesis
Despite this overwhelming consensus, or perhaps
because of it, there are many uncertainties and flaws
of reasoning in this hypothesis on epidemiological,
clinical and microbiological grounds. Epidemiologi-
cally, the data presented above falsify the assumption
that AIDS is spreading in general populations in the
USA and UK by heterosexual transmission ofHIV. The
salient point that AIDS was described (Gottlieb, 1981;
and see report from the CDC, Atlanta, Ga., from Cal-
ifornia State Health Department and from New York
City, Dept. of Health) simultaneously in California and
in New York City as focal incidents, with no evidence
of anything comparable elsewhere at that time, is often
overlooked. The first cases were registered in San Fran-
cisco on July 1st, 1981. By March 1985, 1,000 cases

had been registered, of which 992 (99%) were male and
98% homosexual or bisexual with multiple partners,
with a very high prevalence of gonorrhoea, syphilis,
hepatitis and other sexually-transmissible infections,
with 13% using intravenous drugs and 98% resident in
the Bay area. The position in 1992, in the UK, most of
Europe, Australasia and North America at least, is that
AIDS is still predominantly a disease of men (Table
2) and that the women who acquire it, at a much low-
er incidence, are those who expose themselves to high
risks of infections from partners with AIDS or at risk of
AIDS because of homosexual and bisexual behaviour,
and from use of toxic drugs.
In female prostitutes, who are a risk group for any
sexually-transmitted disease (STD), HIV infection and
AIDS are prevalent in African cities (see WHO: week-
ly epidemiological reports) but not in North America
or Europe unless they use drugs habitually or have
other STDs. Seale (1988) suggested that, for this rea-
son, AIDS did not qualify clinically for classification
as an STD, and also because it is essentially 'A blood-
borne infection which is transmitted only with consid-
erable difficulty during biological sexual intercourse'
- from which he excluded penile-anal intercourse.
This would be consistent with the findings, in multi-
center prospective and many other studies (Marmor,
Friedman-Kien & Laubenstein, 1982; Shilts, 1987;
Gunzburg, Fleming & Millar, 1988; Detels, English &
Visscher, 1989; Ma & Armstrong, 1989; Beral, Bull
& Darby, 1990) of homosexual men, that rectal trau-
ma and infections from bleeding, douching, fisting and
other traumatic and ano-erotic acts are associated with
progression to AIDS and ARCs.
In Africa, the Caribbean and Asia, notifications of
seropositivity to HIV and of AIDS to the WHO are
increasing sharply. The epidemiological and clinical
patterns, at face value, are different from those of the
western world. Cases are reported with equal frequen-
cy in males and females and homosexuality and use
of drugs are uncommon as risk factors. In place of the
opportunistic infections reported in developed coun-
tries, tuberculosis, diarrhoeal diseases, malnutrition,
exhaustion and early death are the main clinical fea-
tures. Occurring as they do on a considerable scale
in young men and women, this is widely regarded as
a new, uncontrollable epidemic in many sub-Saharan
countries. Details of CD4 counts, isolation of HIV and
other tests are seldom available.
There is considerable genetic divergence in the
comparatively small number of strains of HIV iso-
lated in third world countries (Louwagie, McCutchan
169
& Van der Groen, 1992; Pfutzner, Dietrich & von
Eichel, 1992). As in the USA and Europe, AIDS is very
uneven in distribution. Originally, it was reported from
Uganda (Serwadda, Sewankambo & Carswell, 1985)
as a localised, wasting 'Slim' disease, but now it has
become an acute infection strongly linked with tuber-
culosis (Konotey-Uhulu, 1989; Berkley, Widi-Wirski
& Odware, 1989; de Cock et ai., 1992). Along with
other STDs, AIDS is increasingly prevalent in certain
cities on the international travel routes of persons who
sample the local risks, and convey their own infec-
tions and risk-behaviour to local populations. Hence
the ominous spread in Africa via truck-routes, and
in the UK in certain immigrants, visitors, returning
travellers and their domestic partners (Hawkes et ai.,
1992).
AIDS was not described in Africa until 1984, some
years after the first occurrences in white men in the
USA and in black Haitian immigrants in New York
City. This, together with the prevalence of seroposi-
tivity to HIV in unconfirmed ELISA tests in Zaire in
1985, led the consensus to the belief (Gallo, 1987;
Mann, 1989) that AIDS had therefore originated in
Africa. A wide search was therefore made to find sup-
port for a subsidiary hypothesis that AIDS had spread
somehow from Africa to the USA, if not to the rest
of the world. The reasoning is that HIVs evolved
like Simian Immune Deficiency Viruses (SIVs) latter-
ly identified in non-human primates in Africa, either
by phylogenetic separation of a retrovirus from a com-
mon progenitor in the distant past, or by cross-species
transfer to humans more recently (McClure & Schultz,
1989). If this is shown to be genetically plausible, or
if immune deficiency occurs naturally in non-human
primates infected with SIVs, or artifically with HIV in
the absence of other infections, the argument might
become credible. But a very extensive search has
revealed no common progenitor, and no link between
any SIV and HIV 1 in Africa (Seale, 1988). Irrespec-
ti ve ofthe simian or other origins of HIV s the view that
AIDS in the clinical pattern now observed was already
prevalent in Africa is entirely speCUlative. There is
no comparable study of the alternative possibility that
AIDS might have travelled from its observed origin in
the USA in 1981 somehow to Africa.
Classification of AIDS
AIDS is registered internationally as if it were a single
infectious disease, and is surveyed accordingly, that
170
is to say as if it were a self-defining dependent vari-
able. But the original empirical classification by the
US/CDC accepted internationally in 1983 was expand-
ed in 1987 to schedule a range of neoplasms, infections,
malnutrition and dementia in which seropositivity to
HIV, with or without risk-group identification, or these
symptoms without seropositivity in risk groups were
made eligible for classification as AIDS. This increased
the size of the epidemic in the USA by about 27%. To
this list of 'indicator' diseases, a further revision in
1992, synchronous with identical changes in the Inter-
national Classification of Diseases, added cancer of
the cervix, tuberculosis and other diseases in persons
who are seropositive. This has already added numer-
ous females to the incidence of AIDS (Fig. 1) and
manufactured an epidemic in women which is, other-
wise, conspicuous by its absence (Stewart, 1992b). To
add to the confusion, there are growing doubts (Cou-
ruce, Muller & Richard, 1986; Meyer & Panker, 1987;
Midthum, Garrison & Clements, 1990; Mortimer,
1991; Davey, Dayton & Metcalf, 1992; Papadopulos-
Eleopoulos, Turner & Papadimitriou, 1992) about the
lack of an independent gold-standard validator, and
therefore about the specificity of sero-tests for HIV,
even with double testing by immune-absorption and
blot, in the presence of other infections and immuno-
logical disorders, especially in tropical countries. The
fall in CD4 lymphocytes, required for validation, but
seldom performed outside specialised units, is also a
non-specific event (Drew, Mills & Levy, 1985; Jason,
Holman & Evatt, 1990; Root-Bernstein, 1993) which
occurs in many other infections and after infusions of
foreign protein, e.g. to haemophiliacs (Carr, Edmond
& Prescott, 1984).
Clinical diagnosis
In centres with expertise and facilities, surveillance of
AIDS is monitored, with appropriate checks and tests.
In reports from such centres, the pattern of AIDS is
consistent and predictable, as above. But HIVs can be
isolated from persons with and without AIDS or related
conditions (ARCs). The great majority of seropositives
show no signs of disease. To accommodate the contin-
uing absence of AIDS in such persons, the 'incubation'
period between infection and the onset of disease has
been extended to 15 years or more in the 1987 and
subsequent classifications by the CDC and WHO. This
had led to a muddled situation in which anyone with
the wide spectrum of symptoms and signs in these var-
ious classifications who has antibodies to antigens in
anyone of the several antigen-kits. or a fall in CD4
counts, is liable to be diagnosed as AIDS: so are per-
son in risk groups with some of the signs, whether
or not they are seropositive, and seronegatives not in
risk-groups with signs who then become seropositive.
The Revised Classification now in use raises to 28 (in
Section B20-24) the number of independent diagnoses
that may now be registered as AIDS. Section B21.0-9
includes 6 specified and 3 unspecified malignancies, to
which cancer of the cervix is now added. This alone
has already added thousands of cases of AIDS to sur-
vey totals of AIDS internationally. Section B21.7-9
(any cancer) and B22 (any other specified or wasting
disease) in anyone who happens to be seropositive and
in many who are not. add many more. Details of col-
lateral or co-incidental disease, and tests to exclude
other diagnoses are not required for registration, not
even the CD4 (T4) lymphocyte count, mandated by the
consensus as the hallmark of AIDS. Against all logic,
this extraordinary diagnostic gallimaufry is accepted
by the medical profession and the consensus as input
data, not only for surveillance, but also for prediction
of the spread of AIDS internationally.
Microbiology
HIVs have several properties which may relate to
the pathogenesis of AIDS (Gallo, 1987, Fauci, 1988;
Evans, 1989a). In addition to the gag, pol andenv genes
common to all retroviruses, they have five or more non-
structural genes including a tat master-switch (Carlin,
Peterlin & Derse, 1992; Elangovan, Subramanian &
Chinnadurai, 1992) which enable them to regulate
their replication and to delete, insert and duplicate
nucleotides so as to evade immune responses. They
are naturally lymphotropic and enter T-helper lympho-
cytes. among other cells, because their envelope gly-
coproteins interact with specific CD4 surface receptors
(Dalgleish, Beverley & Clapham, 1985). In situ, they
transcribe their RNA into the cell's DNA and replicate
to form virions which have been shown to infect mono-
cytes and macrophages as direct transfer (Fauci, 1988;
Li & Burrell, 1992; Innocenti, Ottoman & Morand,
1992). These migrate to other sites, including the brain
and thymus. where HIV may infect other cells, remain
latent or replicate in accordance with the interplay of
positive and negative regulatory elements in its own
genome, or in those of defensive cells.

Retroviruses are characteristically latent (Dues-
berg, 1987; and see Hanafusa, Pinter & Pullman,
1989). HIV is no exception in the great majority of
infected persons who remain, to date, asymptomatic.
But this unusual combination of genetic heterogeneity
and antigenic variability between strains of HIV, with
mutability of nucleotide sequences within strains and
tropism for migrant cells, would seem to offer plausible
mechanisms for activation. In a search for amino acid
sequences involved in cell tropism, Cheesebro et al.
(1992) found homology in macrophage-tropic clones
from different patients. T-cell-tropic clones were, in
contrast, highly heterogeneous. Site-specific mutations
in amino acid sequences in the V3 region of HIV iso-
lates appeared to be responsible for these tropisms.
This hypervariable domain within gp 120 is recognised
(Shioda & Levy, 1992) as a major determinant of the
ability of HIV-l to infect T-cells and macrophages.
These and other examples of genetic heterogeneity
occur within as well as between strains, so much so that
HIV has been described as a quasi-species in which no
two genomes are identical (Wain-Hobson, 1989; Var-
tamian, Meyerhans & Wain-Hobson, 1992). Many are
defective and, by the same token, non-infective. Provi-
ral sequences vary accordingly, in the same or in suc-
cessive isolates, and so do replication rates in vivo, as
disease advances. The consensus accepts these prop-
erties of HIV as explanations of its ability to emerge
from latency and of its pathogenicity. The impetus of
over 60,000 supportive papers since 1983 is formidable
even though much of it depends upon results obtained
and elaborated in vitro. There is, as in other branches of
biomedical research, a greater focus on the behaviour
of the microbe than on that of the host.
The only prominent retrovirologist to question the
consensus about HIV is P.H. Duesberg of the Depart-
ment of Molecular Biology at Berkeley, CA, whose
dissent is absolute. He considers that HIV is as inactive
in patients with AIDS as it is in asymptomatic carriers.
In fact, he goes further and rejects the wider claim by
most virologists that latent viruses and mutated genes
can be pathogenic (Duesberg & Schwartz, 1992). His
arguments, dating from 1973 and extending far beyond
the virology of AIDS, are set out in papers (1987,
1989a) and responses to criticisms (1989b, c). His
main argument, as a retrovirologist, is directed against
the central dogma that mv infects, multiplies in and
kills enough T-helper lymphocytes to destroy immuni-
ty. His observations that, in patients with AIDS, only 1
in 500 T-cells ever contain a provirus of HIV and that
HIV cannot kill these cells have been confirmed inde-
171
pendently by Lemaitre et al. (1990), the team which
originally isolated HIV. His assertions that neutralis-
ing antibodies restrict multiplication of mv, and that
it does not have the biological energy or biochemical
capacity to produce pathological changes in vivo have
been disputed (Blattner, Gallo & Tenin, 1988; Balti-
more & Feinberg, 1989; Evans, 1989a, b; Weiss &
Jaffe, 1990) but not falsified. He offers evidence that,
when latent viruses are reactivated after neutralisation
by antibodies, this is due to independent factors (other
infections, immunosuppressive conditions) and not to
mutations in the coding region of the virus. He applies
this view to other retroviruses and diseases no less than
to HIV. If he is correct, or even partially correct, the
implications will be revolutionary, for they will dismiss
as circumstantial the current beliefs that latent viruses
cause specific, progressive infections and that mutat-
ed oncogenes can ever cause cancer. HIV would then
be merely a marker for AIDS while cancers would be
more likely to arise from clonal chromosomal abnor-
malities.
In his original (invited) contribution to this field in
1987, Duesberg made a critical analysis of the facts
and gaps in retrovirology in this regard. But in reject-
ing HIV as the cause, he also attacked the core of the
biomedical research on AIDS. This led, after a consid-
erable delay, to polarised reprisals with a minimum of
reasoned debate (Blattner, Gallo & Tenin, 1988; AAAS
Policy Forum, 1988) on his main question about the
cytopathic effect of HIV. This is still unresolved. Even
so, Duesberg would be wrong in rejecting a pathogenic
role for HIV on this account alone because as Chees"
boro et al. (1992), among others, have shown it can
unquestionably infect monocytes and macrophages by
cell-to-cell transmission, without killing them, and
then travel in them to other tissues where the presence
of infected cells would be enough to arouse inflamma-
tory response and hence disease, e.g., a glial response
in the brain. If there was already a latent infection with
Toxoplasma, this could multiply to cause encephalopa-
thy which is reported in about 30% of patients with
cerebral AIDS (Root-Bernstein, 1993). When defini-
tive signs of AIDS develop, HIV replicates and releases
antigen (Ho, Pomerantz & Kaplan, 1987). It is insisted
(Fauci, 1988; Baltimore & Feinberg, 1989; Weiss &
Jaffe, 1990) that this is due to a regulated change from
latency to accelerated replication, but it might equal-
ly be part of the general multiplication of organisms
which occur in any immunosuppressive state, and is a
main contributor to death in AIDS.
172
Duesberg's rejection of the claim that HN kills
lymphocytes per se is supported by the work of
Lemaitre, Montagnier and their colleagues (1990)
showing that the cytocidal effect of two archetypal
strains ofHIVs (LAV-Bru ofHN-l and Rod ofHN-
2) in vitro was lost in the presence of non-inhibitory
concentrations of tetracycline analogues. Since these
compounds do not interfere with the infectivity of
HNs, the likelihood is that a tetracycline-sensitive
organism, now confirmed as a mycoplasma, plays the
role of synergistic co-factor in HIV-induced cell lysis.
It is now thought to be identical to Mycoplasma Jer-
mentans (incognitus) previously isolated by Lo (1986)
from patients with AIDS. This mycoplasma has been
visualised, isolated in culture and identified by DNA
probes in thymus, lymph nodes, spleen, liver, brain and
placenta of patients with AIDS and from HN-negative
patients with fulminant necrotising lesions or fatal dis-
ease in these organs. Most of the isolates were made
from tissues without necrotic or inflammatory changes
but ultra-structural examination showed, in some cas-
es, intracellular mycoplasma and cytopathic changes
in lesions from which no other pathogens were visu-
alised or isolated. When injected into four monkeys,
the mycoplasma caused systemic infection followed by
wasting and death in 7-9 months with necrotic lesions
without inflammatory reaction in which the mycoplas-
ma (originally thought to be a virus-like agent VLIA)
was identified by immunochemistry, in situ hybridis-
ation and electron microscopy (Lo, Wang & Newton,
1989). DNA from M. Jermentans has been detected
in the blood of seropositive patients (Hawkins et at.,
1992) but, in a systematic study of patients attending
an SID clinic, Katseni, Gilroy and Ryait (1993) found
it also in peripheral blood mononuclears, throat swabs
and urine from a majority of seronegative as well as
seropositive homosexual men. This is unrelated to the
stage of disease, CD4 count and cellular HIV load in
the seropositive subjects.
Mycoplasmas are notorious as contaminants in tis-
sue cultures, especially those requiring reinforcement.
It is surprising that they have not been reported in
the innumerable other laboratories which are working
round the clock internationally with HIVs from many
sources. Coming as they do from the scientists who dis-
covered HN, the results quoted above prove that HIV
cannot kill T-lymphocytes without assistance from a
mycoplasma. The work of Lo and his colleagues sug-
gests, but does not prove, that this organism may have
a synergistic or pathogenic role in AIDS.
The image of HN as a universal pathogen is weak-
ened further by the fact that the strains isolated in the
USA and Britain were merely subcultures of the orig-
inal strain (LAV-I ) isolated in 1983 from a gland from
a patient in Paris. Genuine independent isolates show
continuous diversification (Shioda & Levy, 1992; Var-
tamian, Meyerhans & Wain-Hobson, 1992; Spencer,
et aI., 1994). The strain type HN-l is uncommon or
absent in some populations with AIDS in Europe and
Africa, and is not cross-reactive with some prevailing
strains (Quinn, Piot & MacCormick, 1987; Zwart, de
long & Wolfs, 1990). Genetic heterogeneity and diver-
gent sub-types of HIV on a wider scale, as reported
above from Africa and India, might explain the vari-
ability in symptomatology and progression of AIDS.
By the same token, this means that some strains are
likely to be less, or much less pathogenic: a prospect
already verified by the survival of the majority of
infected persons in the USA and Europe. The consen-
sus views that all who are infected will develop AIDS
and probably die is falsified on this score alone.
In the weeks after infection with HIV, some persons
develop a brief illness with fever and lymphadenopa-
thy, similar to infectious mononucleosis. Seroconver-
sion then occurs, producing antibodies to HN enve-
lope proteins gp 120 and p24. The majority of infected
persons remain asymptomatic but a minority, identifi-
able in terms of risk-behaviour and exposure to further
infections, show the hallmark fall in CD41ymphocytes
with reversal of the T4ff8 ratio, lymphadenopathy,
anergy, loss of immunity, multiplication of infection
organisms including HIV, and other signs of ARCs or
AIDS. From then on, AIDS seems to be irreversible,
despite specific anti-viral and symptomatic treatment.
The main pathological findings are pneumonias (Pneu-
mocystis carinii or acute bacterial), gastro-intestinal
infections (Candida, salmonellae, shigellae, entamoe-
bae), co-incident or secondary infections of the skin,
viscera and brain with other pathogenic and oppor-
tunistic bacteria, fungi and protozoa (Table 4); and,
mainly in homosexual men, Kaposi's sarcoma. Some
or all of these, along with failing nutrition and exhaus-
tion,lead usually to early death, though mortality since
1983 has decreased considerably in developed coun-
tries (D' Arminio, Vago & Lazzarin, 1992).
Baemophilia
The occurrence of serpositivity to HIV and of AIDS
following transfusions of infected blood and blood

Table 4. Infections associated with deficiency of immunity, including indicator
diagnosis of AIDS according to the criteria (l}-(4) of the Centers for Disease
Control, Atlanta, Ga.
Infecting organism
Viruses:
Cytomegalo-
Epstein-Barr
hepatitis
herpes
Molluscum contagiousum
Papova
Varicella-zoster
Mycoplasma
Bacteria
Mimea-herrelea
Mycobacteriumavia spp
do kansasii
do tuberculosis
Steptococcus moniliformis
non-typhoid salmonella
hemophilus
pyogenic
Fungi
Aspergillus spp
Candida albicans
coccidiomycoses
Cryptococcusneoformans
Histoplasma capsulatum
Nocardia spp.
Protozoa:
Cryptosporidia
Entamoeba histolytica
Giardia lamblia
Isospora spp.
Leishmania donovani
Pneumocystis carinii
Strongyloides spp.
Toxoplasma gondii
·(1) Gross inspection/microscopy. (2) Microscopy. (3) Microscopy, culture, serol-
ogy, detection of antigen or DNA in body fluid or tissue. (4) Culture.
products in some haemophiliacs and other patients,
and the apparent cessation of this after donors were
screened and blood sterilised by heat, have been
advanced as self-evident and conclusive proof of the
causation of AIDS by HIV (Tsoulkas et al., 1984; Lud-
lam, Tucker & Steel, 1985; Hiltgartner, 1987; Ward,
Bush & Perkins, 1989; Darby, Rizza & Doll, 1989).
173
Diagnosis· Localising signs
1 and 4 +
2 hepatic, neurological.
3 lymphadenomas
3 hepatic
3 cutaneous, genital, ocular
3 cutaneous
3 genital, cutaneous
3 muco-cutaneous, ocular
2,3 systemic
4 +
3 pulmonary or systemic
2,3 granulomata
2 pulm, dermal, lymphatic
1,2,3 pulm., extra-pulm.
2 pharyngeal, pulmonary
1,3 enteritis, septicemia
3 in children only
1,3 abscesses
4 +
3 pulmonary
1,3 esophagitis
3 pulmonary, systemic
3 neurological
2,3 pulmonary
pulmonary
2 +
enteritis, malabsorption
1,4 colitis
enteritis
enteritis
1,3,4 cutaneous, visceral
1 pulmonary
2 intestinal
encephalitis
The existence of seroconversion and signs compat-
ible with AIDS in recipients of transfusions, especial-
ly in haemophiliacs, is not in doubt. But this has to
be considered against background facts. Blood trans-
fusions are, by themselves, well-known to be tem-
porarily immuno-suppressive. Patients receiving fre-
quent transfusions are, by definition, in a risk category.
Mortality, even in the short term, is often high, inde-
174
pendently of the HIV status of donors and recipients
(Ward, Bush & Perkins, 1989). Repeated transfusions
were shown by Carr, Edmond and Prescott (1984)
to cause lymphocytopenia, abnormalities in subsets
of lymphocytes including decreased or inverted T-
helperlsuppressor ratios, low NK cells, and abnormal-
ities in B-cells and immunoglobulins. These changes
are much more marked in haemophiliacs receiving fre-
quent injections of Factors VIII or IX concentrated
commercially from large pools of whole blood from
thousands of donors. Prior to concentration and anti-
viral treatment of blood, many patients had received,
not only HIV, but other blood-borne organisms, some
of which (CMV, HSV, EBV, HBV, VZV) multiply read-
ily in any state of immuno-suppression and aggravate
progression to AIDS in persons at risk (Webster, Lee
& Cook, 1989; Makris, Preston & Triger, 1990; Root-
Bernstein, 1993).
Sources of infection in pooled blood are not easily
identified. Ludlam and his colleagues (1985) followed
a cohort of 32 haemophiliac men in Edinburgh who
received HIV, identified subsequently by RNA/PCR
assay in a single batch of Factor VIII of intermediate
purity. Ofthese 32, 18 became seropositive to HIV and
12 developed immunological abnormalities and signs
2-6 years later 'attributable to HIV infection', includ-
ing six deaths. Cell-free circulating virus was found
in both asymptomatic and symptomatic patients, but
signs of illness (CDC-IV) were confined to those with
a prevalent haplotype Al B8 DR3 already associated
with immunological hyper-reactivity (Steel, Beatson
& Cuthbert, 1988; Medical Research Council, 1990).
The 14/32 who remained seronegative in 1993 showed
no signs of ARCs or AIDS. There were no secondary
cases of HIV or AIDS in female sex partners (Ludlam,
1993).
In a randomised three-year study, Seremetics,
Aledort and Sacks (1990) found that the CD4
count remained high in 20 asymptomatic seropostiive
patients who received a monoclonally-purified Fac-
tor VIII, but fell significantly (P < 0.001) in 15 who
received a standard product of intermediate purity. One
patient in each group developed signs of AIDS. Like-
wise, de Biasi, Rocino and Miraglia (1991) reported a
fall in CD4 cells in 10 seropositive haemophiliacs who
received standard Factor VIII of intermediate puri-
ty after 96 weeks, but not in 10 similar seropositive
patients in whom treatment was switched to a product
purified by binding with monoclonal antibody. Only
2/10 in this group became anergic and none devel-
oped ARC signs, whereas in the other group 9/10
became anergic and two developed signs (CDC-III).
Since high-purity Factor VIII and Factor IX are now
replacing all others, a follow up of these cohorts is
essential for therapeutic as well as for aetiological
implications.
Female partners of seropositive haemophiliac men
may sero-convert within a year of presumed exposure,
but this is variable and has been shown by Ragni and
her colleagues (1987, 1989) and by Jin, Cleveland
and Kauffman (1989) to be not significantly related to
frequency of intercourse, condom use or immunologi-
cal abnormalities. The rate of secondary transmission
appears to be below 25% overall, and of subsequent
AIDS 0-20%. It is surprising that, in the many surveys
of HIV infection and AIDS in haemophilia, and in
an official, collaborative, prospective study in Britain,
there is little or no reference to this vital aspect of trans-
mission and control of infection. However, the virtual
absence of ARCs and AIDS in other surveys (Mar-
cus, 1988) of tens of thousands of health professionals
exposed to needle-stick injuries, lesions and body flu-
ids in the routine care for patients with AIDS and HIV
seropositives show that, with one questionable excep-
tion (Lancet, 1992) the pathogenicity of HIV, even
when transmitted, is minimal or absent in persons who
are immuno-competent, in contrast with that of hepati-
tis B which is so readily transmitted that immunisation
is now a routine for clinical personnel.
These and many other studies define a risk pop-
ulation of haemophiliac and a very small minority
of other patients who may sero-convert after transfu-
sions of infected blood or blood products, and an even
smaller subset who develop signs of AIDS and die.
The transfusion and haemophiliac data do not prove
that HIV causes AIDS because foreign proteins in
repeated or concentrated transfusions cause immuno-
suppression and similar changes independently ofHIY.
In haemophiliacs and other patients with pre-existing
defects in immunity (see Immune activation, below),
this allowed HIV and other organisms - prior to safe-
ty measures introduced in 1985 - to multiply. The
outcome was variable, but secondary transmission of
AIDS and ARCs has been minimal.
Rejection of HIV as the unique cause of AIDS
HIV can be transmitted, though not readily, in sexu-
al secretions and whole blood or blood products, and
causes viraemia, lymphadenopathy and a prolonged,
usually latent infection of lymphoid and other tissues.

This can be diagnosed, and is now classifiable as HIV-
disease. But the collateral hypothesis that the array
of complex disorders diagnosed as AIDS are unique-
ly caused by HIV is flawed a priori by the circular
argument which mandates indirect evidence of infec-
tion with HIV (i.e. seropositivity) as the main crite-
rion for diagnosis, and by a contrived classification
which preferentially schedules as AIDS common con-
ditions occurring independently in persons who are
seropositive whether or not they belong to risk groups.
Diagnosis is therefore wide open to subjective errors,
confusing options and misinterpretations which are not
corrected in international surveillance except in centres
where expertise and standardisation are available. The
dependent variable used for epidemiological input is
therefore unreliably subjective. Analyses of data are
impeded by failure to allow for confounding variables
such as alternative diagnoses, false-positive serology,
coincident infections, toxic drugs, sexual practices and
other factors which emerge consistently in surveillance
as determinants. The hypothesis has not offered an ade-
quate defence against competent criticisms of some of
its integral genetic and microbiological tenets. Its offi-
cial projections and predictions are falsified, especially
those postulating a pandemic of fatal disease spread by
heterosexual transmission in the general populations of
developed countries. It depends, for continuance as in
its origin, on denial of the logic of a decade of surveil-
lance data and on subordination of open thinking to
a consensus of circular thinking about the mandated
correlation between HIV and AIDS which refuses to
tolerate interrogation.
An ALTERNATIVE HYPOTHESIS is proposed,
suggesting that although HIV can cause lym-
phadenopathy and serconversion (HIV Disease), as
stated above, the origin, pathogenesis and spread of
AIDS can be better understood and explained as fol-
lows:
AIDS became an instant diagnostic entity in 1982
because the first cases died - as most of their successors
still do - with two rare but conspicuous terminal dis-
orders, Kaposi's sarcoma (KS) and pneumonia due to
protozoan Pneumocystis carinii (PCP), together with
buccal and oesophageal candidiasis, amoebiasis, tox-
oplasmosis and other well-recognised but unfamiliar
infections with pathogenic or opportunistic organisms.
These, with signs of immune deficiency, cachexia and
fatality in young homosexual men and drug addicts,
constituted a novel and dramatic clinical event, well
described by Gottlieb, Friedman-Kien, Sonnabend and
other early investigators (Root-Bernstein, 1993), and
175
promptly recognised as an emergency by the U.S.
CDC. But is was confined to these groups of men
whose lifestyles had, in an explosion of high-risk sex-
ual activity and use of toxic and euphoriant drugs,
exposed then repeatedly to high risks of genital, rec-
tal and blood-borne infections in places and practices
which are best described by insiders (Shilts, 1987).
Genital, rectal, intestinal, pulmonary and systemic
infections acquired in this way reflect the local human
and environmental microflora of latent and active
pathogens, facultative pathogens and commensals
(Table 4), long associated with cell-mediated immu-
nity and now accepted for classification as indicators
of AIDS. The resulting diseases vary accordingly, in
pattern and severity, in different localities and regions.
They comprise infections, re-infections and multiple
infections which soon undermine immunity and vital-
ity. HIVs are prominent but not unique members of a
group of viral invaders (CMV, EBV, HSV, HBV, HCV,
VZ and possibly HTLVs), all of which may impair
cell-mediated immunity (Root-Bernstein, 1993). Sim-
ilar clinical states are seen in lympho-proliferativedis-
orders, reticuloses, graft-versus-host rejections, auto-
immune conditions, malignancies, irradiation, protein-
calorie malnutrition, syphilis, and especially in inter-
actions and intoxications due to drugs.
In AIDS, the original and most prominent routes of
transmission are firmly linked to self-selected and self-
propelled behaviour, namely penetrative anal inter-
course and sometimes other forms of sexual con-
tact, especially when traumatic or promiscuous, use
of drugs, or both. These produce infections locally and
in the blood stream, and are the primary and necessary,
though not sufficient, cause of the majority of cases
of AIDS registered in the USA, Europe and Australa-
sia. Multiple local and systemic infections thus con-
veyed, including HIV, undermine immunity, interfere
with healing and nutrition and depress vitality. These
infections, especially with continuing risk behaviour,
are sufficient to explain much of the pathogenesis in the
two main risk groups of homosexual and bisexual men
and needle-sharing drug users. AIDS in other persons
- risk-sharing partners of cases, babies, recipients of
transfusions - result from secondary transmission of
infections and antecedent weakness or dysregulation
of immunity as in infancy, genetic defects, haemophil-
ia, use of drugs and malnutrition. But some of this was
happening before AIDS appeared in its contemporary
form, so additional explanation is required.
176
Homosexual and bisexual behaviour
Male homosexual relationships without anal inter-
course or injections of drugs - arguably the majori-
ty (Ma & Armstrong, 1989; Stewart, 1990b) - are
not associated with AIDS; neither is lesbianism. AIDS
began and prevailed among those who are still at high-
est risk, namely the passive male, and sometimes
female, recipients of anal intercourse. This is because
the rectal mucosa and its supporting tissues are relati ve-
ly fragile, designed for excretory, not intrusive activity.
When the thin submucosa is eroded and blood vessels
damaged, the tissues and blood stream are opened to
invasion by all the organisms of the faecal microflora.
by the pathogens of all the sexually transmitted dis-
eases, and many others. The risk of trauma and infec-
tions increases greatly with the frequency, variety (oro-
anal, lingua-vaginal) and violence of the sexual activ-
ity and preference, as with 'fisting' and other accesso-
ry, traumatic and contaminating procedures, and with
multiplicity of partners (Witkins & Sonnabend, 1983;
Mavligit, Talpag & Hsia, 1984; Moss, Osmond &
Bacchetti, 1987; Winkelstein, Wiley & Padian, 1988;
Sonnabend, 1989).
In such persons, the unregulated use of antimicro-
bial drugs for self-treatment of gonorrhoea and other
infections inhibits the competitive flora of the intes-
tine, opening it to bacterial and fungal super-infections
which are indicator conditions for diagnosis of AIDS.
Notable among these are Pneumocystis carin ii, Can-
dida albicans, cryptosporidia and organisms causing
chronic diarrhoea, and hence dehydration, loss of
electrolytes and exhaustion. The frequent presence of
semen in the rectum and blood adds allogenic, 'non-
self' reactions which dysregulate immune responses
(Witkin & Sonnabend, 1983; Root-Bernstein, 1993).
The faecal microflora interacts with semen to form
N-nitrosocompounds, some of which are immunosup-
pressive and carcinogenic (Schoental, 1988). Immuno-
suppression also occurs (Newell, Mansell & Spitz,
1985; Mirvish & Haverkos, 1987; Vandenbrone & Par-
doel, 1989) from the use of volatile alkyl nitrites (pop-
pers) as aphrodisiacs and relaxants - an effect which
conveniently extends to the rectal sphincter. In exper-
imental animals, these nitrosating agents are lympho-
toxic, causing immuno-suppression followed by death
from acute and chronic infections. Surviving animals
sometimes develop lymphomas (Schoental, 1988). It is
possible that the conjunction of N-nitroso compounds
from semen with volatile nitrites contribute to Kaposi's
sarcoma which occurs in this context independently of
HIV (Beral, Bull & Darby, 1990). All this, combined
with frequent, promiscuous anal and bisexual inter-
course with dozens or hundreds of partners had become
a way of life in the dedicated communities in which
AIDS was first observed and in those (of remarkably
similar persuasions and micro-flora) to which it quick-
ly spread, internationally. Knowledge of the dangers
sometimes led to a reduction in risk-behaviour but, by
this time, genital and other infectious diseases were
accepted as features of their way of life.
Transmission in heterosexuals
This is regarded by the WHO and the consensus as
the usual mode of transmission of AIDS in many
third world countries. In North America and Europe,
surveillance shows some increase in AIDS occurring in
both sexes from presumed heterosexual transmission
but, in the UK and USA at least, the increase is fraction-
al, even in persons with high risk partners (Tables 2 and
3) and in those attending SID clinics, and is confined
to major urban areas. It is uncommon in prostitutes
unless they are using drugs. AIDS in women outside
the main risk groups is minimal or zero. Since seropos-
itivity to HIV in random samples may be equal in the
sexes, and since sexual intercourse with more than one
partner by the age of 18 is now common, the key ques-
tions arising from the absence or infrequency of AIDS
in females are if and why it occurs at all. Confiden-
tiality of records and lack of contact-tracing deemed
necessary in other SIDs preclude answers. How much
of what there is has been acquired from bisexual men,
from anal intercourse, from undeclared use of drugs?
But a thorough search of registration data in key areas
of the USA and UK (Stewart, 1992a, 1993a) and of
a vast international literature (Root-Bernstein, 1993)
discloses no convincing reports of outbreaks of AIDS
in females exempt from risk-behaviour or from cir-
cumstances which impose risks upon them.
Use of psychoactive and immuno-toxic drugs
An amalgam of debilitating infectious and wasting
disease had been noted from the late 1960s onward
in young adults and adolescents who injected them-
selves repeatedly with impure and unsterile, illegally-
obtained psychoactive drugs (Gay, 1972; Moss, 1987;
Selwyn, 1989). This practice causes bizarre, often
intractable infections in the blood and various organs

from contaminants in the drugs. Needle-sharing,
promiscuous sexual intercourse and general disre-
gard of hygiene - a notorious feature of the drug
scene everywhere - leads to sharing also of whatev-
er infections are endemic in that community - PCP,
HIV, hepatitis, herpes, EBV, VZ and CMV which
may impair cell-mediated immunity and reverse T4fT8
ratios (Louria, Hensle & Rose, 1967, McDonough,
Madden & Falek, 1980; Drew, Mills & Levy, 1985;
Creglev & Mark, 1986; Moss, 1987). All the psycho-
active drugs currently in use in this way, especial-
ly heroin and experimental mixtures, are profoundly
depressing to appetite, general health and immuni-
ty. Cocaine and crack damage the respitory ephithe-
lium which is a main barrier to all air-borne infections.
Alternation of excitement and depression leads quick-
ly to habituation, overdosage and reckless disregard of
all the personal and societal consequences of this life
style.
Drug use has been escalating in conurbations in
the USA for 25 years, and is now the main reason for
heterosexual spread of AIDS (Moss, 1987) there and
in many other countries. If infection is minimised by
using uncontaminated drugs and needles, or especially
by opting for less toxic oral drugs such as methadone,
many addicts can live equably with their habit for many
years (Capel, Goldsmith & Stewart, 1972; Creglav
& Mark, 1986). Otherwise, chronic infection, espe-
cially with therapy-resistant protozoa and fungi, leads
to severe disease in target organs and often to death.
A pregnant woman in this state transmits her infec-
tions and her drug-toxicity congenitally to her child. In
some countries, drug addicts donate blood for payment
and transmit their latent or active infections to plasma
pools. Most or all of the extending range of infec-
tions listed as indicators for AIDS (Table 4) and other
microflora from the local environment were perceived,
together with defects in immunity, in persons in these
categories before AIDS appeared. They now include
multi-drug resistant forms of tuberculosis. The illegal
use of drugs is also diversifying as a predictable but
usually uncontrollable disaster in large and growing
sectors of youth and young adults in the conurbations
of the western world. HIV was well-established in this
population internationally by 1985, and is continuing
to spread within it.
177
Immune system activation
HIV differs from non-retroviral infections because of
the affinity between glycoprotein 120 on the surface
of the virus and CD4 receptors on T-cells. This facil-
itates entry of HIV into a minority of cells and ini-
tiates a generalised immune response: activation of
T-cells, lymphadenopathy, antibodies to envelope pro-
teins, antigen-specific tolerance, neutralisation of virus
and latency of infection. The HIV hypothesis, postu-
lating reactivation of virus by internal regulation and
destruction of immunity by killing ofT-helper lympho-
cytes is falsified by the fact that immunity is sufficient
to arrest replication of virus and delay onset of fur-
ther disease, in the absence of risk behaviour, by ten
years or more. The usual signal of advance of dis-
ease is not viral replication, but a continuing fall in
CD4 lymphocytes. In so far as it can occur in oth-
er infections, in graft-host disease and in disordered
immunity, this is a largely non-specific event. But it
is a significant event in AIDS because it is associated
with the appearance of lympho-cytotoxic antibodies
(LCTAs) acting against non-HLA antigens and periph-
eral blood B- and T-Iymphocytes in some haemophil-
iac and homosexual patients (Pruzanski, Jacobs &
Laing, 1983; Kiprov, Anderson & Morand, 1985;
Ozturk, Koller & Horsburgh, 1987; Stricker, McHugh
& Moody, 1987; Daniel, Schimpf & Opelz, 1989).
These occur in seronegative and seropositive patients,
but are much more prevalent in the latter and in homo-
sexual and haemophiliac patients with AIDS. They are
cross-reactive with major histocompatibility (MHC)
class II proteins on B- and T-cells, with spermatozoal
antigens (Ashida & Schofield, 1987; Root-Bernstein
& Hobbs, 1991) and with antigens from C.albicans,
the cause of the oro-oesophageal infection which was
and is a main and early indicator for AIDS.
Male homosexuals have anti-spermatozoal anti-
bodies in the blood, which cross-react with T-cells
and have been linked to the occurrence of azoosper-
.,mia and testicular atrophy in homosexual men (Adams,
Donovan-Brand & Friedman-Kien, 1988; Ma & Arm-
strong, 1989). The same antibodies have been detect-
ed in female patients with AIDS (Sheppard & Asch-
er, 1990) and are cross-reactive with T-cells and HIV
antibodies. The common factor is obviously anal inter-
course, a main risk-factor for female as for male AIDS.
These cross-reactions reflect a mixed state of allogenic
and auto-immunity in which patients, with and with-
out HIV, reject their own T-cells because they can-
not distinguish them from antigens from spermato-
178
zoa, HIV, other infections, foreign proteins and cells
in transfusions and in injection needles used for street
drugs. This explains the selective incidence of AIDS in
homosexual men, in women with bisexual partners or
who engage in anal intercourse, and in haemophiliacs,
some of whom would be additionally at risk because of
innate disorders of immune regulation or of immuno-
suppression by drugs.
Sheppard and Ascher (1988, 1990, 1992) go fur-
ther. They see the pathogenesis of AIDS as the out-
come of two sets of signals acting on T-cells in a
continuous process of immune activation. The first
(specific) signal comes from the interaction of a T-
cell receptor with an antigenic peptide presented as
an MHC molecule following infection with HIV. The
second signal is non-specific and is provided by se1f-
molecules on cells which react with other T-cell recep-
tors and regulate the activation produced by the first.
Most of the progeny of the activated cells (lympho-
cytes and thymocytes) are eliminated by 'programmed
death' (apoptosis) which restores the immune system
to equilibrium (Zacharchuk, Mercep & Chakraborti,
1990), but a minority remain as 'memory' cells in
a resting state in which they retain their capacity to
respond to an appropriate stimulus (Beverly, 1991).
This may come in various ways: in HIV infection,
from activation ofT-cells by interaction of gp120 with
CD4, leading to lymphadenopathy and non-specific
auto-immune responses. The shift toward programmed
cell death then causes a fall in CD4 cells (McClure &
Dalgleish, 1992). But there is evidence also of antigen
tolerance by clonal deletion of reactive thymocytes and
of B-cells of the spleen, by activity of superantigens
(Quarantino, Murison & Knyba, 1991) which act on
VB regions of T-cell receptors, and by what Shep-
pard and Ascher (1992) call a 'paradoxically-intense
response' to peptides involved in allo-reactivity. It is
likely that some of the many drugs used in the treat-
ment of AIDS contribute to this. The outcome depends
also on the frequency of exposure to antigens and on
the ability of HIV quasi-species to induce the second
signal.
One of the well-recognised immunological anoma-
lies in AIDS (Duesberg, 1989) is that HIV can only
replicate in the antigen-presenting T-cells which it sup-
presses. These cells multiply during the period of gen-
eral immune activation in the onset of infection, and
accept the gp 120/CD4-TCR antigen complex (Dal-
gleish, Wilson & Gompels, 1992), after which they
decrease. This is restricted to subsets with MHC Class
II allo-determinants which mimic HIV-l, supporting
the likelihood that the response is auto-immune, sim-
ilar to that in graft-v-host disease, in persons in VB
subfamilies with selective HLA-associated suscepti-
bility to HIV-l (Fabio, Scorza & Lazzarin, 1992).
In a comprehensive investigation of the immunolo-
gy, Root-Bernstein suggests (1992, 1993) that this
response is a multiple antigen-mediated auto-immunity
(MAMA) provoked by the various infections, drugs
and allo-antigens. These theories offer an explanation
of the mechanism of immune activation, but they do
not explain the long periods of latency which may fol-
low.
The evidence from this active immunological front
presents AIDS in many patients as an auto-immune dis-
ease precipitated by rejection ofT-helper lymphocytes
and thymocytes in complicated cross-reactions with
any or all of several antigens, and in se1f-nonself dis-
crimination (von Boehmer & Kisielow, 1990; Sprent,
Gao & Webb, 1990) in persons in genetically sus-
ceptible SUb-populations. This results in an upset of
immunological tolerance and a suppression of cell-
mediated immunity to the point where it can no
longer cope with additional infections. With sper-
matozoa as allo-antigens and drugs as independent
immuno-suppressants included, and with the immuno-
reactive haplotypes in Caucasian populations defined,
this would seem to be sufficient to explain much, if
not all, ofthe pathogenesis as well as the selective and
continuing incidence of AIDS almost exclusively in
subsets of populations in defined risk groups in North
America, Europe and Australasia.
The need for an alternative hypothesis
This has been raised on several occasions especially
by Duesberg (1987, 1989), Sonnabend (1989), Evans
(1989a) and by the author (1989, 1992a). Sonnabend,
working with patients in Manhattan, was the first to
explain the vunerability of homosexual men, in partic-
ular the effect of spermatozoa in the rectum on immu-
nity. He suggested that risk factors for seroconver-
sion are different from those for AIDS in which auto-
immunisation, release of interferon, massive inocula
in tranfused blood and blood-products, and a trigger
effect of coincident viral infections might account for
the pathogenesis of ARCs and AIDS.

Conclusion
An alternative hypothesis must explain not only the
pathogenesis of immune deficiency in AIDS, but also
the pattern of transmission and epidemiology. In the
hypothesis presented here, AIDS is presented as a dis-
ease acquired in the first place by self-preferred or
imposed behaviours, which in themselves dysregulate
immunity and homeostasis while also leading to expo-
sure to various pathogenic and opportunistic infections.
The complex syndrome which follows has infectious,
immunological and metabolic features. The hypothesis
rejects HIV as a unique and sufficient cause of all this
but agrees that it is transmissible in sexual secretions
and blood, causing HIV disease: lymphadenopathy and
febrile illness followed by latency or minimal patho-
logical change during which there is evidence of direct
cell-to-cell transmission of virus to migrant mononu-
clears and neural cells, of direct encephalopathy and
of immune activation.
AIDS and AIDS-related complexes (ARCs) devel-
op, with and without HIV, because heterologous anti-
gens in spermatozoa enter the rectum and bloodstream,
or in whole blood and blood concentrates given as
transfusions, provoke allogenic responses and elicit
antibodies which are toxic to lymphocytes, and cause
a fall in CD4 counts. HIV can do the same by joining
with CD4 receptors on T-helper lymphocytes presented
along with MHC Class II proteins because of molec-
ular affinities. This complex is tolerated, because it
is recognisable at first as self, so HIV survives in
clones of activated lymphocytes and monocytes in
the presence of neutralising antibodies. But repeat-
ed infections of the genital, alimentary and respiratory
tracts conveyed with various heterologous antigens,
as above, maintain the T-cell activation while anti-
lymphocyte antibodies are being formed. This leads
to auto-immunity with a fall in CD4 count, reversal
of the T4rr8 ratio, anergy and programmed cell death
of T- and B-Iymphocytes, consistent with the collapse
of immunity, and atrophy of thymic and splenic folli-
cles found post-mortem in patients dying with AIDS.
It explains the general absence of AIDS in immuno-
competent persons, the special susceptibility of homo-
sexual men and haemophiliacs, and the risk to the foe-
tus of a mother with AIDS; and it is entirely consistent
with the epidemiological pattern of AIDS in the USA
and most of Europe to date.
The occurrence of AIDS in drug users is
attributable, firstly, to the general immunosuppressive
properties of most of the major psycho-active drugs
179
at present in use and secondly, to contaminants and
impurities which cause refractory infections and dys-
regulate immunity. Persons in this risk category often
overlap with the male homosexual group. Girls and
women place themselves at high risk by taking drugs
or by having intercourse with men in high risk groups.
If they are pregnant, their infants share these risks
by intra-uterine or perinatal exposure. Otherwise, the
spread of AIDS by heterosexual transmission in either
direction is minimal or absent except in sub-Saharan
Africa where registrations are increasing rapidly, but
in a totally different clinical and epidemiological pat-
tern which overlaps with other, prevalent infections
and with malnutrition.
Predictions made on this basis are accurate to with-
in 10% of registered totals of current and cumulative
incidence in the USA and UK. The risk-behaviour
hypothesis postulates that, for these reasons, AIDS
will continue to occur in persons and communities
in defined susceptibility groups although HIV disease
will be much more widely prevalent. Along with other
organisms (HSV, CMV, VZ, EBV, various protozoa,
fungi and bacteria), HIV can be activated from laten-
cy by various forms of risk behaviour, as described
above, because this leads to an overload of genital,
alimentary, pulmonary and systemic infections com-
pounded by dysregulation of natural immunity, either
by spermatozoa in the rectum .and blood in persons
of either sex experiencing traumatic anal intercourse,
or from organisms acquired in oral sex, or from the
immuno-toxic effects of injected or ingested drugs or
from self-medication by broad-spectrum antimicrobial
agents or, frequently, from all of these in life-styles
which disregard elementary rules of hygiene and nutri-
tion. In persons choosing these life-styles, AIDS is
essentially a self-inflicted disease which can only be
prevented by awareness and self-control. For persons
upon whom these risks are inflicted, one way or anoth-
er, it is becoming increasingly and tragically obvious
that protection is imperative.
Impact of this new hypothesis on research and
control of AIDS
The monopolistic hypothesis that HIV-l is the unique
cause of AIDS has, since 1984, led not only to erro-
neous predictions, but also to widespread misinforma-
tion and grotesque errors in prognosis, treatment, allo-
cation of resources and strategy for research (Rubin,
1988; Adams, 1988; Eigen, 1989; Stewart, 1989,
180
1992a; Craven, Stewart & Taghavi, 1994). Resources
and funds for the longer term are allocated mainly for
single-factor strategy based on the false assumptions
(Montagnier, 1994) that a specific vaccine or drug will
eliminate or cure AIDS. Even if this were possible, the
ethical and logistic problems would be immense. To
whom would the vaccine be given? Would recipients
be encouraged to continue risk-behaviour? How else
would exposure and efficacy be measured? Or will the
vaccine or vaccines be used as shot-guns on the blind
guess that everyone is already at risk? Since hetero-
sexual spread is not occurring in developed countries
on anything approaching the scale envisaged in offi-
cial predictions, it is easy to see how a vaccine used
widely at this stage could be given credit for control of
a pandemic which is not occurring. On the drug front,
the consensus jumped the gun by promoting the use
of Azidothymidine (AZT, Zidovudine), a highly cyto-
toxic drug, for prophylaxis in seropositive pregnant
women and infants on the assumption that without
it, they would all develop AIDS and die. This pol-
icy continues, despite the evidence in the prolonged
Anglo-French Trial (Aboulker & Swart, 1993; Con-
corde, 1994) which showed no significant prophylactic
effect in symptom-free HIV-positive subjects in terms
of survival or disease progression after five years.
If the HIV hypothesis is inadequate or wrong, the
risks and misplacement of effort and research since
1984 will be enormous. The alternative hypothesis
offered here differentiates HIV infection and disease
from AIDS which, in developed countries at least, is
a complex amalgam of diseases determined first and
foremost by high risk behaviour in subsets of popula-
tions in restricted social, ethnic and geographic loca-
tions. It postulates that prevention depends essentially
upon recognition and control of these existential deter-
minants by education, notification, contact tracing and,
if necessary, by legal constraints upon behaviour which
p!aC~S unaware or passive persons, including unborn
infants, at equally high or higher risks. The situation
in the developing world is even more serious but is
different in ways which cannot be understood without
a more informative data-base about the distribution
and pattern of AIDS and other life-threatening and
sexually-transmitted diseases, and about life styles in
affected countries.
The data and predictions supporting the alternative
risk-behaviour hypothesis are presented here in a man-
ner which opens them in the short term to falsification
and correction, for instance, by factual data exclud-
ing other diagnoses and confirming the occurrence
of destruction of immunity with unremitting signs of
AIDS and HI-viraemia by secondary transmissions to
and between persons not engaging in risk-behaviour,
or in infants of seropositive mothers not exposed to
direct or indirect risks.
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Five myths about AIDS that have misdirected research and treatment

Robert S. Root-Bernstein
Department of Physiology, Michigan State University, East Lansing, M148824, USA

Received 15 February 1994 Accepted 14 June 1994

Key words: AIDS progression, HIV seroreversion, HIV vaccination, behavioural risks, etiology

Abstract

A number of widely repeated and factually incorrect myths have pervaded the AIDS research literature, misdirecting
research and treatment. Five of the most outstanding are: 1) that all risk groups develop AIDS at the same rate
following HIV infection; 2) that there are no true seroreversions following HIV infection; 3) that antibody is
protective against HIV infection; 4) that the only way to treat AIDS effectively is through retroviral therapies; and
5) that since HIV is so highly correlated with AIDS incidence, it must be the sole necessary and sufficient cause
of AIDS. A huge body of research, reviewed in this paper, demonstrates the falsity of these myths. 1) The average
number of years between HIV infection and AIDS is greater than 20 years for mild hemophiliacs, 14 years for young
severe hemophiliacs, 10 years for old severe hemophiliacs, 10 years for homosexual men, 6 years for transfusion
patients of all ages, 2 years for transplant patients, and 6 months for perinatally infected infants. These differences
can only be explained in terms of risk-group associated cofactors. 2) Seroreversions are common. Between 10 and
20 percent of HIV-seronegative people in high risk groups have T-cell immunity to HIV, and may have had one or
more verified positive HIV antibody tests in the past. 3) Antibody, far from being protective against HIV, appears to
be highly diagnostic ofloss of immune regulation of HIV, and some evidence of antibody-enhancement of infection
exists. 4) Non-retroviral treatments of HIV infection, including safer sex practices, elimination of drug use, high
nutrient diets, and limited reexposure to HIV and its cofactors have proven to be effective means of preventing or
delaying onset of AIDS. 5) Many immunosuppressive factors, including drug use, multiple concurrent infections,
and exposure to alloantigens, are as highly correlated with AIDS risk groups as HIV. These data are more consistent
with AIDS being a multifactorial or synergistic disease than a monofactorial one.

Introduction
Many commentators on AIDS have neatly divided the
AIDS world into those who believe that HIV is the
sole necessary and sufficient cause of AIDS, and those
who believe that it plays no role in AIDS at all. In
fact, many investigators believe that HIV definite-
ly plays some role in AIDS, but that its role is as
yet undefined. Whether it is necessary but not suffi-
cient to cause AIDS, one of the many factors acting
synergistically, or a player in the induction of lym-
photoxic autoimmune processes is still an open ques-
tion (Buimovici-Klein et al., 1988; Donohoe & Falek,
1988; Duesberg, 1987, 1989, 1990, 1992; Fernandez-
Cruz et al., 1988; Haverkos, 1988; Hoff & Peterson,
1989; Hoff et al., 1991; Kion & Hoffmann, 1991; Lit-
tlefield, 1992; Lo et al., 1991; Lusso, Lori & Gallo,
1990; Macon et aI., 1993; Mathe, 1992; McClean &
NOWak, 1992; Montagnier et aI., 1990; Papadopulos-
Eleopulos, 1988; Pifer et al., 1987; Root-Bernstein,
1990a, 1990b, 1990c, 1992a, 1992b, 1993, 1994;
Root-Bernstein & Hobbs, 1993; Root-Bernstein &
DeWitt, 1994; Rubin, 1988, Shearer & Levy, 1984;
Sonnabend & Saadoun, 1984; Sonnabend, Witkin &
Portillo, 1984; Sonnabend, 1989, Stott, 1991; Wang et
al., 1992; Ziegler & Stites, 1986).
The crucial point for any theory of AIDS is to
account for not only the presence of HIV and anti-
bodies to it in the vast majority of AIDS patients, but
also why some people develop all of the symptoms
186
of AIDS in the absence of HIV, why others remain
healthy for decades after HIV infection and may even
serorevert, and why the time between HIV infection
and full-blown (CDC stage 4) disease varies tremen-
dously between patients. I will argue that neither the
theory that HIV is necessary and sufficient, nor the
theory that it is irrelevant to understanding AIDS, is
satisfactory for explaining AIDS because both theo-
ries are based upon misleading, but widely held myths
about the disease and about how biomedical research
should best demonstrate the cause(s) of AIDS.
Five myths, in particular, are often repeated in the
medical literature, and are demonstrably incorrect: 1)
that all risk groups develop AIDS at the same rate fol-
lowing HIV infection; 2) that there are no true serore-
versions following HIV infection; 3) that antibody is
protective against HIV infection; 4) that the only way
to treat AIDS effectively is through retroviral therapies;
and 5) that since HIV is so highly correlated with AIDS
incidence, it must be the sole necessary and sufficient
cause of AIDS. We will not be able to understand and
effectively treat AIDS until these myths are exploded
and the facts of AIDS installed in their place.
Myth 1: HIV progresses to AIDS at the same rate
in all risk groups
The most powerful and often-cited argument against
the need for cofactors and for the sufficiency of HIV
is that people in all risk groups progress to AIDS at
the same rate following HIV infection. Roy Anderson,
for example, states, 'The median incubation period
of AIDS (time from infection to the development of
AIDS) appears to be approximately 10 years in sexu-
ally active adults in developed countries irrespective
of risk group' (Anderson, 1993). He, James Curran
and many others have argued from such evidence that
cofactors associated with particular risk groups can-
not have any effect of AIDS progression. Similarly,
Robin Weiss states that the development of AIDS is a
purely 'stochastic process' and agrees with Anderson
'that population groups with different lifestyles have
similar rates of progression to AIDS' (Weiss, 1993, his
Fig. 2; see my Fig. 1). The one admitted exception are
hemophiliacs under the age of 25 who progress more
slowly to AIDS than other groups. Weiss claims, how-
ever, that after a lag period, they have 'a similar rate of
progression to AIDS' as all other risk groups (Weiss,
1993). A review of the relevant literature casts doubt
on these crucial claims, however, and thereby on the
implication that cofactors are irrelevant to AIDS pro-
gression.
Weiss, Anderson, and Curran have evidently failed
to examine all of the available studies, or have not
paid attention to sophisticated mathematical models of
epidemics. For one thing, most hemophilia studies dif-
ferentiate between hemophiliacs age 25-44 and those
over the age of 44, because the rate of AIDS develop-
ment in the over 44 group is two or four times faster
than that of the 25-44 age group. Weiss can make
hemophiliacs have the same rate of AIDS progression
as homosexual men only by lumping the 25-44 and
over 44 age group together. (Weiss, 1993). Further-
more, reference to a large body of studies not cited
by Weiss or Anderson reveals a rate of progression to
AIDS among hemophiliacs less than 25 years of age
that is significantly different from that found in Figure
2 of Weiss's article, and with a slope different than that
for homosexual and hemophiliac men in general (Fig.
1) (Darby et at., 1990; Schinaia et at., 1991; Sorice et
at., 1989; Giesecke et at., 1988; Eyster et at., 1987).
The discrepancy in the two sets of data is due to
reliance by most experts (including Weiss, Anderson,
and Curran) on studies performed at hemophilia treat-
ment centers (HTCs) in the United States and Britain.
HTCs see only a fraction of all hemophiliacs, gener-
ally the most severe cases, but do not see symptom-
free hemophiliacs (Stehr-Green et at., 1989; Eyster
et at., 1987). The majority of the patients studied in
the references cited by Weiss (1993), for example, are
severe type A hemophiliacs (see Lorenzo et ai., 1993
for another example in which 64% of the cohort had
severe disease and had exactly the rate of development
predicted by Weiss). Less than a third of hemophili-
acs have severe disease, however, and the incidence
of AIDS in mild hemophiliacs is 117 that of severe
hemophiliacs (Goedert et ai., 1989; Hardy et ai., 1985).
Thus, incubation periods based on severe hemophili-
acs overestimates rate of progression to AIDS, and
are not representative of all hemophiliacs (Giesecke
et ai., 1988). Severity of hemophilia is independent-
ly predictive of development of AIDS, possibly due
to increased frequency of use of clotting concentrates,
transfusions, viral contaminants, and steroidal, col-
loidal gold, and opiate drugs associated with joint
injury treatment (Rosendaal, Smit & Briet, 1991; Root-
Bernstein, 1993). In consequence, several studies have
shown that reliance on data from HTCs results in large
overestimates of rates of AIDS and of total numbers
of AIDS cases among hemophiliacs (Stehr-Green et
aI., 1989; Eyster et aI., 1987). Overall, only about 15

o+-~~-r--~--~~--~--~~~~
o 2 3 4 5 6 7 8 9 activity, or both, have significantly decreased rates of
YEARS
Fig. 1. Proportion of individuals surviving without AIDS plotted
with data combined from various European and North American
studies detailed in the text: HIV- homosexual men and hemophiliacs
" (Weiss, 1993); HIV+ homosexual men and hemophiliacs over
the age of 25 0 (Weiss, 1993); HIV+ hemophiliacs under the age
of 25 0 (Weiss, 1993); HIV + hemophiliacs under the age of 25 •
(this study); HIV + blood transfusion patients 'f (this study); HIV+
transplant patients. (this study); HIV+ pediatric patients. (this
study). Note that no study of HIV + transplant patients larger than 25
has been performed so that statistical variation in reported AIDS-free
survival times vary much more widely than in studies of other risk
groups. In order to indicate the variation, bars have been added to
the transplant patient points indicating the range of reported data,
and the points themselves are drawn from a single large study of
22 patients by Lang et al. (1991). Note the tailing off of AIDS risk
with increasing length of AIDS-free time in infants and transplant
patients. I predict that a similar tailing off will cause all other risk
groups to have rates of AIDS that become sigmoidal.
percent of HIV infected hemophiliacs have developed
AIDS in the United States and the United Kingdom
at present (CDC, 1993), although one would expect
over 40 percent according to the rates of development
projected by Anderson and Weiss (Weiss, 1993; Stehr-
Green et al., 1989).
Further data also contradict the current dogma con-
cerning rate of disease development. Weiss and many
other investigators attribute the lower rate of devel-
opment of AIDS in young hemophiliacs to age. Per-
haps, he conjectures 'younger persons have greater
CD4lymphocyte reserves and precursors for renewal'
(Weiss, 1993; see also Goedert et ai., 1989). Studies of
people infected with mv through transfusions prove
187
this conjecture wrong. Transfusion patients younger
than 5 years of age develop AIDS significantly faster
than older children, while children over the age of2 but
under 13 years of age develop AIDS at almost exactly
the same rate as people between the ages of 13 and 39
and between 40 and 60 (Lui et al., 1986; Medley et
al., 1987; Wang & See, 1992; Krasinski, Borkowsky
& Holzman, 1989; Kopec-Schrader et aI., 1993). Only
people over the age of 59 have a rate of AIDS onset that
is shorter than that of younger patients, and the differ-
ence is not statistically significant (Kopec-Schrader et
al., 1993). Weiss's conjecture also fails to address why
hemophiliacs over the age of 44 should have great-
ly increased rates of progression to AIDS compared
with 25-44 year olds when such a phenomenon is not
apparent in transfusion patients, nor can it explain why
hemophilic men age 20 to 44 years who have addi-
tional risk factors such as drug abuse, homosexual
survival (Holman et al., 1992). Moreover, no one has
ever reported that age affects the rate of progress to
AIDS among HIV infected homosexual men, although
a substantial number of these men contract the disease
either prior to the age of 25 or after their 44th year. I
presume that no age effect has been reported among
gay men because no such effect exists although I can
find no studies specifically addressing this question.
Those who claim that AIDS develops at the same
rate in all risk groups also ignore data showing that
transfusion patients of all ages develop AIDS at a
significantly greater rate (50 percent have AIDS an
average of 5.5 to 7.0 years after infection) (Lui et al.,
1986; Medley et al., 1987; Ward et al., 1989; Downs
et al., 1991; Msellati et al., 1990; Kopec-Schrader et
al., 1993) than do homosexual men or hemophiliacs
(an average of ca. 10 years or more). Moreover, the
slope of the progression for transfusion patients dif-
fers from that seen for homosexual men or hemophil-
iacs (Figure 1), indicating that the increased rate is
not due simply to fewer T-cells at the time of infec-
tion, but rather to ongoing synergistic effects with oth-
er factors. These factors include the disease process
that required surgery in the first place, infection with,
or reactivation of, latent immunosuppressive infec-
tions including cytomegalovirus, Epstein-Barr virus,
and hepatitis viruses, the immunosuppressive effects
of anaesthetics, opiate analgesics, chronic and high
dose antibiotics, and (following some types of surgery)
malnutrition, not to mention chronic health problems
that often follow major surgery (reviewed in Root-
Bernstein, 1990a, <\1991, 1992, 1993).
188
The proof that immunologic status and ongoing
exogenous immune suppression are determinants of
progression to AIDS comes from studies of organ
transplant patients who are infected with HIV (and
often other viruses and bacteria) at the time of their
operation (Fig. 1). Fifty percent of these patients devel-
op AIDS within 1.2 to 2.8 years, depending on the
types of transplant and the type of immunosuppressive
treatment they receive (Cooper et al., 1993; Schwarz
etal., 1993; Ribot & Eslami, 1992; Lange eta/., 1991;
Tzakis et al., 1990; Atkinson et al., 1987).
It is clear from all of the published studies that
the type of immunosuppressive regimen used to con-
trol transplant rejection has a very significant effect
on the rate at which AIDS develops and on sur-
vival, but different investigators have found contradic-
tory results concerning the influence of cyclosporine.
Lang et al. (1991) found that four year survival of
HIV+ transplant patients treated with the triple drug
therapy (azathioprine + steroids + cyclosporine) was
19% compared with 57% in HIV+ patients without
cyclosporine. Schwarz et at. (1993), however, have
reviewed published cases and claim that the cumula-
tive incidence of AIDS (not survival!) after 5 years
was 31 % in patients treated with cyclosporine versus
90% in those receiving immunosuppressive treatments
other than cyclosporine. These data may be compati-
ble if one considers the possibility that patients treated
with cyclosporine do not generally live long enough to
develop AIDS, or that their risk of other forms of death
are increased so that AIDS is a less probable diagno-
sis. Indeed, one problem evaluating all data concern-
ing transplant patients is the very high rate of mortality
among these patients regardless of their HIV status.
For example, mean survival time for HIV+ dialysis
patients, most of whom were intravenous drug abusers
in this particular study, was found to be a mere 1.5
years - too short for most of them to develop AIDS
(Lang et al., 1991). On the other hand, kidney trans-
plant patients who must return to dialysis because of
transplant failure have much better odds of survival
than those whose transplanted kidney remains func-
tional (Lang et at., 1991), suggesting that treatments
such as plasmapheresis, which have been reported to
help some AIDS patients, may indeed be effective. In
any event, Lang et al. (1991) summarize their study
with words that aptly convey the conclusions of all
of the cited transplant studies by saying that 'survival
is much lower than in non transplanted patients con-
taminated through blood transfusion ... This shorter
survival is due to both a reduced AIDS-free time peri-
od and an accelerated course between the diagnosis
of AIDS and death.' Clearly, then, chronic treatment
with known immunosuppressive agents demonstrably
and quite dramatically speeds up the rate of onset of
AIDS.
The conclusion that chronic immunosuppressive
treatments increase the rate of AIDS development is
confirmed by studies of patients who are treated for
combined Hodgkin's disease-HIV infection, and have
an average AIDS-free time of only 3 years as a result of
cancer chemotherapy (Roithmann et at., 1993). Blood
transfusions are also known to be acutely immuno-
suppressive, and are often given to AIDS patients
to correct anti-retroviral-induced anaemia. Some evi-
dence suggests that this practice increases the rate at
which AIDS progresses (Vamvakas & Kaplan, 1993).
One might expect that other immunosuppressive treat-
ments, such as systemic corticosteroids for autoim-
mune conditions, will also be found to be contraindi-
cated for people at risk for AIDS. On the other hand,
non-immunosuppressive medical treatments have little
effect on AIDS progression, as has been demonstrated
by a study ofHIV-infected individuals who require car-
diopulmonary bypass surgery (Aris, Pomar & Saura,
1993).
Finally, although everyone knows that perinatally
infected infants have the fastest rate of progression of
any risk group (Weiss, 1993), the huge magnitude of
the rate of increase (median of 6 months) (Fig. 1) is
often ignored (Blanche et al., 1990; Minkoff et al.,
1987; Mayers et at., 1991; Kraskinski, Borkowsky
& Holzmann, 1989). This huge increase in rate of
AIDS progression has never been explained adequately
except in terms of predisposing immunological debili-
tation caused by maternal cofactors experienced by the
fetus or newborn. These factors include drug addic-
tion, multiple concurrent viral and bacterial infections,
exposure to blood products and anaesthetics, malnu-
trition and anemia. A very large proportion of children
who develop AIDS are also significantly premature,
underweight for their age, jaundiced, and malnour-
ished - all factors associated with immune suppres-
sion even in HIV-seronegative infants (ibid.; Ruben-
stein et at., 1983; reviewed in Root-Bernstein, 1990a,
c, 1992, 1993).
I conclude that arguments as to the sufficiency of
HIV as the cause of AIDS are not supported by epi-
demiological evidence. Different risk groups progress
to AIDS at substantially different rates, as do dif-
ferent individuals within risk groups. The so-called
age factor in hemophiliacs is unique to this group,

and must therefore be related to the very significant
changes in the treatment of hemophilia over the past
few decades (e.g., the switch from heavily virus con-
taminated plasma, to less contaminated factor concen-
trate, to ultrapurified and recombinant DNA derived
clotting factor), which has saved young hemophili-
acs from many cumulative immunosuppressive cofac-
tors that affect older hemophiliacs (Rosendall, Smit &
Briet, 1991; Root-Bernstein, 1990a, 1993). Cofactors
known to cause immune suppression and to signifi-
cantly increase the rates of AIDS development, which
are also known to be much more common in older than
younger hemophiliacs, include infections (sometimes
chronic) with herpes viruses, hepatitis virus types B
and C, and cytomegalovirus (Sullivan et ai., 1986;
Goedert et al., 1989; Webster et ai., 1989; Higgins
& Goodall, 1991; Sabin et al., 1993) and exposure to
alloantigens in impure factor concentrates themselves
(Hilgartner et al., 1993; Schulman, 1991; Goedert et
ai., 1989; Sullivan et ai., 1986). All of these cofac-
tors are also present in other AIDS risk groups at
unusually high rates compared to the general popu-
lation (Root-Bernstein, 1993). Attenuation or elimi-
nation of these cofactor exposures through changes in
hemophilia treatment since the 1960s resulted in a rise
in the average life expectancy of hemophiliacs from
33 years in 1960 to nearly 57 years in 1980 (Aronson,
1988; Rosendaal, Smit & Briet, 1991). (Life expectan-
cy has unfortunately plunged again to 40 years dur-
ing the period 1987-1989 due primarily to AIDS, but
also to increases in non-AIDS-associated pathologies
as well [Lorenzo, et ai., 1993; Mares, Sartori & Giro-
lami, 1992; Ritter, 1994]).
One crucial study that would help to clarify the
rate-of-progression issue has not yet been done, and
that is to examine the rate of AIDS onset in spouses
of HIV-positive hemophiliacs and blood transfusion
patients as a function both of HIV infection and
cofactor acquisition (e.g., exposure to hepatitis virus-
es, cytomegalovirus, etc.). Presumably, spouses who
acquire HIV heterosexually and have no drug or medi-
cal problems of their own will have the longest AIDS-
free time of any group yet studied. Only two studies
have been carried out that are relevant to this issue
(Peterman et ai., 1988; Andes, Rangan & Wulff, 1989),
but neither calculates rate of onset of AIDS, nor gives
the elapsed time from HlV exposure. Notably, how-
ever, of four women who contracted HlV from their
hemophiliac husbands prior to 1985, none had devel-
oped AIDS by 1989 and only one had developed AIDS-
related complex in one study (Andes, Rangan & Wulff,
189
1989), while in the other study, one of 12 spouses had
died of AIDS, three had developed lymphadenopathy,
and eight had remained asymptomatic by 1988 (Peter-
man et ai., 1988). If one AIDS case out of 16 infections
over four to eight years is an approximately accurate
interpretation of these results, then the rate of AIDS
onset among this group is, indeed, very low.
One interesting observation that has not been made
before is that the rate of onset of AIDS in infants and
transplant patients appears to level off after a few years,
suggesting that those HIV-infected people who remain
AIDS-free for extended periods of time have an ever-
decreasing probability of developing AIDS. The data
are not yet conclusive on this point, but if it is true,
then one may predict that the probability of developing
AIDS in all HlV+ risk groups will come to resemble
sigmoidal curves. Long-term HIV+ survivors in all risk
groups will, in other words, become less and less likely
to develop AIDS. One indication that such a trend has
already begun comes from a study of HIV+ gay men in
Los Angeles which found that among those infected in
1979,28% developed AIDS within six years, whereas
among those infected in 1983,25% developed AIDS
within six years (Taylor, Kuo & Detels, 1991). The
authors of the study suggest three possible explana-
tions: mutation of HIV toward less pathogenic strains;
better health care for pre-AIDS HIV-infected individ-
uals; or control of cofactors through safer sex, clean
needle, and education programs. The phenomenon of
ever-slowing progression to AIDS has been observed
in homosexual and bisexual men in Amsterdam as well,
where the hazard rate has been decreasing consistently
(Hendriks et al., 1993).
It is important to stress that cofactor models of
AIDS are completely consistent with current data con-
cerning AIDS. In fact, several mathematical models
of AIDS epidemiology demonstrate that the observed
rates of development in each risk group can be
explained only by models involving two or more syn-
ergistic agents. Weyer and Eggers (1990), for exam-
ple, show that even if one assumes the rates of AIDS
onset to be the same for each risk group, the 'drastic
overrepresentation of the sexually highly active groups
and drug abusers in the number of AIDS cases obvi-
ously requires that the transmission of AIDS unequiv-
ocally depends on the sexual and drug risk ... The
observed parallel time series for the spread of AIDS
in groups with different risk of infection can be real-
ized by computer simulation, if one assumes that the
outbreak of full-blown AIDS oniy occurs if HIV and a
certain infectious coagent (cofactor) are present. Such
190
a situation is not uncommon, see, e.g., the influen-
za virus-Staphylococcus aureus system.' Similarly,
McClean and Nowak (1992) have produced a math-
ematical model of AIDS in which HIV forms diverse
quasi-species that have specificities for different T-cell
clones and which can be activated synergistically by
other T-cell-affecting agents (cofactors). While these
authors claim that the criteria necessary to satisfy their
models are not satisfied by existing data - i.e., that
rates of AIDS progression do not differ with differ-
ent risk groups or the presence or absence of known
coinfections - this paper and previous reviews of the
literature (Root-Bernstein, 1990a, b, c, 1993; Root-
Bernstein & Hobbs, 1993) have shown conclusively
that these criteria are met, and that the cofactor model
is therefore accurate and tenable.
Myth 2: Once infected with HIV, always infected
withHIV
A second myth that has misdirected research and treat-
ment for nearly a decade is the oft-stated belief that
once a person is infected with HIV he or she will
remain infected until death. No one, to put the myth in
a different way, beats an HIV infection.
The basis of the belief that HIV infections are irre-
versible apparently comes largely from the experience
of major cohort studies in the United States and Europe,
and from a detailed study of the issue by the United
States Armed Forces. The first large scale study to
report any examples of HIV seropositive individuals
who subsequently seroreverted to HIV negative status
was by Farzadegan and his colleagues of The Multi-
center AIDS Cohort Study (USA) (Farzadegan et al.,
1988). They found that four of 4,954 men participating
in the study seroreverted over a 2.5 year period. All four
men had been demonstrated to have an HIV infection
by ELISA, Western blot, and polymerase chain reac-
tion (PCR). All four then lost all signs ofHIV antibody.
Two ofthe four men also became PCR negative. Sim-
ilar results were reported from other cohort studies,
but never published (Barnes, 1988). The authors ofthe
study and other investigators, rather than concluding
that HIV had been defeated, argued instead that these
four cases may have represented a new phenomenon
they called an 'incomplete' infection and attention was
focused not on the good news that these men may not
get AIDS, but rather that two of them remained anti-
body negative but PCR positive and so might inadver-
tently infect someone through blood or semen (Zuck,
1988).
At least one European group questioned whether
the Americans had really seen any true serorever-
sions, arguing that they had no similar examples in
their cohort. The only apparent cases of seroreversion
they had encountered were all due to mixing up of
blood samples or tests (GUrtler, Eberle & Deinhardt,
1989). A subsequent study by the U.S. Army seemed to
confirm the absence of true seroreversion. Army per-
sonnel reviewed 5,446,161 HIV tests that it had per-
formed on 2,580,974 people from 1985 through 1992.
Of 4,911 people with at least one positive HIV test,
only 6 potential cases of seroreversion were found, all
of which were attributed to sample mix-ups. 'Testing
errors' were given as the cause of 26 further individ-
uals whose HIV infections were not confirmed by a
follow-up test. The authors of the study therefore con-
cluded that there is an 'absence of true seroreversion
of HIV-l antibody in seroreacti ve individuals.' (Roy,
Damato & Burke, 1993)
In fact, several dozen well-documented cases of
seroreversion, often accompanied by return to PCR-
negative status, have been published. For example,
in 1985 the case of a woman who had contracted
HIV from her hemophiliac husband (who subsequently
died) was reported. She had tested HIV positive repeat-
edly in January 1984 with a T-cell count of 561 (more
than one standard deviation below normal variation
[Laurence, 1993]). She was seronegative when retest-
ed in April and October of 1984 and April of 1985, and
her T-cell counts were back up to 698 (a 25% increase,
which is within average intrapatient variation [Hughes
et al., 1994]) by October 1984 and remained at that lev-
el through 1985. She was completely healthy when last
reported (September 1986) (Burger & Weiser, 1986),
and no report of illness or her death has appeared since.
Fribourg-Blancreported two cases of seroreversion
in which infection was demonstrated by isolation of
proviral DNA in addition to ELISA and Western blot
methods. One instance involved a heterosexual male
who reported having a single, high risk 'adventure',
and the other instance involved a biological techni-
cian without identifiable risks who sustained a needle-
stick injury while working with HIV-infected mate-
rial (Fribourg-Blanc, 1988). Perrin et al. (1988) also
described two men who had repeated contact with HIV-
seropositive individuals, seroconverted, and devel-
oped HIV-infections confirmed by PCR. They subse-
quently lost all trace of antibody, retained normal T-
cell function, and remained healthy. In addition, most

studies of the accuracy and reliability of Western blot,
immunoprecipitation, and polymerase chain reaction
(PCR) testing report several cases of seroreversion and
loss of detectable virus among groups of tested indi-
viduals of varying sizes (e.g., four of twelve cases in
Jaffe et at., 1985; four in a hundred in Horsburgh et at.,
1990; and one of the 29 in Kniiver-Hopf et at., 1993).
Several very recent reports confirm the existence
of unexpectedly large numbers of seroreverters. Scott
Tanenbaum and Cindy Leissinger, researchers at
Tulane University found five severe hemophiliacs (rep-
resenting 10% of their cohort) with HIV-seropositive
blood samples at one or more time points, all of whom
subsequently seroreverted (Tanenbaum et at., 1993;
Anonymous, 1994). These researchers point out that
between 10% and 15% of severe hemophiliacs who
were probably exposed to HIV-contaminated factor
one or more times have remained seronegative. Indeed
a substantial proportion of people exposed to HIV-
contaminated blood factor lots and blood transfusions
have also been found to be seronegative on later testing.
Henrard et al. (1993), for example, studied 103 high
risk seronegative individuals, including 85 hemophil-
iacs, of whom 52 were known to have been exposed
to HIV-contaminated factor concentrates. Seventy-six
plasma samples (72%) were consistently negative for
HIV-l DNA by PCR; 24 (22%) were positive only
once, but were not so upon multiple retesting; and 4
(3%) were positive twice, and then negative thereafter.
When cellular DNAs were extracted from the blood
specimens ofPRC-positive plasma samples, none were
found to be positive for HIV-l DNA, suggesting that
the plasma-based PCR test has a very high rate of false
positive results when performed on HIV-seronegative
samples. On the other hand, 10 of 10 PCR tests of cel-
lular DNA from HIV-seropositive individuals yield-
ed PCR-positive results. Henrard and his collegues
concluded that HIV-seronegative individuals who are
known to have been exposed to HIV have truly elimi-
nated the retrovirus, and do not remain latently infec-
ted.
It is probable that the results reported by Henrard
et at. (1993), and Tanenbaum et at. (1993) are very
common. Ward and his collegues at the AIDS Pro-
gram of the Centers for Disease Control studied 765
people who received HIV-tainted blood transfusions.
Only about 60% were found to be seropositive with-
in an average of 5 years after exposure (Ward et at.,
1989). Similarly, Ludlum et al. (1985) found that of
34 hemophiliacs transfused an average of over a dozen
times each with a single batch of HIV-contaminated
191
clotting factor VIII concentrate, only 18 became HIV-
seropositive, and the risk was not associated with num-
ber of transfusions since most of the men seroconvert-
ed after receiving only three treatments while others
remained seronegative after more than a dozen.
Similarly, Clerici et al. (1992) have documented
dozens of instances of seronegativity among high risk
individuals, including gay partners of HIV-infected
men who have engaged in repeated acts of unprotected
receptive anal intercourse, health workers exposed to
HIV by subcutaneous cuts and needlestick accidents,
and drug users who have shared needles with HIV-
infected addicts (Brown, 1992). All of these people,
although antibody-negative at the time they were test-
ed, nonetheless displayed active T-cell responses to
HIV antigens, suggesting that they had, in fact, been
infected previously by HIY. Berkeley researchers have
also reported seven healthy people - at least five of
whom were definitely exposed to HIVr- with T-cell
mediated immune responses to HIV, but without HIV
antibody. Two of the seven had urine samples positive
for HIV-antibodies at one time, but seroreverted during
the study (Urnovitz et at., 1993).
In addition, many research groups have reported
that the existence of significant numbers (hundreds
all told) of people who are at least transiently (and
sometimes chronically) PCR-positivefor HIV, but per-
sistently antibody negative (reviewed in Imagawa &
Detels, 1991). These are individuals who have normal
immune responses, with normal antibody production.
While most of these investigators have interpreted their
results as evidence for chronic, latent infection with
HIV, Imagawa and Detels have argued that such data
are more compatible with the concept of transient or
incomplete infection, because subsequent verification
ofPCR positivity at later time periods is often impossi-
ble (ibid.). The transient interpretation is given added
weight by the fact that all of the cases reported have
been healthy individuals.
Documented cases of seroreversion, in sum, appear
to represent the tip of a very large iceberg consist-
ing of thousands of people who have been exposed to
HIV and successfully fought off the infection without
developing antibodies, or who developed antibodies
but seroreverted prior to testing. The reasons for the
iceberg being overlooked can be understood if we now
go back and reanalyze the methods used by large cohort
studies that report extremely low or non-existent sero-
reversion rates. These studies all have major flaws in
their design. First, most cases of seroreversion seem to
occur in people with limited exposure to HIV and who
192
have no ongoing cofactor exposure (Fribourg-Blanc,
1988; Root-Bernstein, 1993). People involved in most
AIDS cohort studies, on the contrary, are by the design
of the studies in high risk groups and very often have
continued exposure to both mv and putative cofactors.
Second, the timing of seroreversion appears to be such
that many people may have been infected with HIV but
seroreverted prior to first being tested for the cohort
study, and some appear to remain HIV-seronegative
during the study despite being exposed to HIV. These
people are not identifiable as having been exposed to
HIV because of the use of antibody tests for initial
screening for infection. Exposure leading to successful
T-cell immunity without antibody cannot be document-
ed without the more tedious efforts of T-cell antigen
recognition studies, which are very rarely performed.
And third, the U.S. Army study is irremediably flawed
by the very fact that their data base consists of confir-
matory tests, which are normally carried out within a
few weeks or months of one another, rather then over
the several years that appear to be necessary for loss of
mv antibodies and elimination of HIV from infected
cells to occur. Thus, the Armed Forces study is not at all
relevant to determining the rate of true seroreversion
(Tanenbaum, Leissinger & Garry, 1993).
Fribourg-Blanc concludes that 'these observations
[of seroreversion] are certainly not rare, but authentifi-
cation of such cases requires conditions that are diffi-
cult to satisfy' . His work, and that of an ever-increasing
number of other investigators tells us that we must stop
assuming that if a person is infected with HIV, they
will necessarily produce antibody, and that following
infection, they will necessarily remain infected forever.
For many people, HIV infection is transient, and such
people hold the keys to understanding how to combat
AIDS.
Myth 3: Antibody to HIV is protective so vaccina-
tion is possible
The third myth that I want to discuss is one that is
shared alike by those who believe that HIV accounts for
all of the immune suppressions in AIDS, and by those
(such as Duesberg) who believe that mv has nothing
to do with AIDS. This myth maintains that antibody
against HIV is protective, and therefore that the pres-
ence of antibody indicates that the retrovirus has ade-
quately been controlled. Duesberg uses this argument
in order to contend that since all AIDS patients have
high levels of antibody against HIV, therefore HIV
cannot be doing any significant damage to the immune
system or body (Duesberg, 1989, 1990). Those who
believe that HIV is the sole cause of AIDS argue, to the
contrary, that if only people can be vaccinated against
HIV so that antibodies are present prior to infection,
then exposure to HIV will carry no risk of AIDS. Old
and new evidence suggests that both of these positions
are wrong.
The most important evidence in this regard has
already been reported under Myth #2 above, and con-
sists of the fact that HIV-seropositivity is usually asso-
ciated with low CD4 counts that rectify themselves
when seroreversion occurs. Additionally, as we have
just seen, a significant proportion of people repeatedly
exposed to HIV become PCR positive but remain anti-
body negative and healthy. Other people repeatedly
exposed to HIV remain antibody negative, are PCR-
negative, but demonstrate T-cell activation toward HIV
antigens, strongly suggesting that they have previously
mounted an effective T-cell response to HIV (or some
cross-reactive alloantigen [Stott, 1991; Kion & Hoff-
man, 1991]). In short, HIV is controlled by the T-cell
response, and antibody positivity to HIV is negatively
correlated with control of HIV infection.
These data strongly suggest that the primary line
of defense, and the only effective one against HIV is a
T-cell response (Clerici et ai., 1992; Clerici & Shearer,
1993; Salk et aI., 1993). T-cell regulation is reason-
ably common for non-cytolytic encapsulated viruses,
and antibody enhancement of infection is relatively
common for these viruses as well (see below). Anti-
body is only produced when T-cell immunity fails to
control viral replication and a sufficient amount of free
virus is present in blood, lymph, or tissues to activate B
cells. Clearly, as the cases of seroreversion prove, this
antibody is short-lived in the absence of active, ongo-
ing infection, and does not remain to protect against
further infection. This phenomenon of rapid loss of
antibody is also consistent with a primarily T-cell reg-
ulated immune response, rather than a primarily B-cell
regulated immune response.
In fact, there exists a class of infectious diseases,
most of which consist of noncytopathic encapsulated
viruses (of which mv is one), the pathological effects
of which are actually exacerbated by the presence of
antibody. One example is lymphocytic choriomeningi-
tis virus (LCMV) infection in mice, which has many
similarities to hepatitis B virus and HIV infection in
man (Oehen, Hengartner & Zinkernagel, 1991). In
LCMV, as in many other viral infections in which the
immune response, rather than the virus infection itself,

causes lymphocyte death, survival is dependent on a
successful T-cell response rather than upon antibody
production. Production of antibody, whether natural-
ly occurring or as a result of vaccination, is highly
associated with death of the animal (Oehen, Hengart-
ner & Zinkernagel, 1991). Dengue virus infection in
human beings presents a similar picture. The severe
hemorrhagic fever associated with the virus is almost
always a result of an anamnestic or secondary anti-
body response. Presence of antibody has been found
to be a strong predictor of severe disease following
reinfection with a variant strain of the virus (Halstead,
1988; Kliks et al., 1989). Since HN mutates very
quickly, and an extremely large number of HIV strains
are known, probability of antibody-mediated enhance-
ment of secondary infection with variant HN strains in
AIDS becomes a very likely event, which may, indeed,
explain the long latency found in the syndrome.
LCMV and dengue virus are only two of
many examples antibody-enhanced disease. Porter-
field (1986) and Burke (1992) have summarized the
relevant data for a very wide range of non-cytopathic
viruses, including dengue, Japanese encephalitis,
yellow fever, tick-borne encephalitis, Sindbis, res-
piratory synctial virus, rabies, reoviruses, murine
cytomegalovirus, corona viruses, and lentiviruses (e.g.
the visna virus of sheep). In some cases, vaccines
(usually live attenuated strains) against these virus-
es have been very effective, but in others, such as
respiratory synctial virus, measles virus, and vis-
na virus, vaccination with formalin-inactivated whole
virus dramatically increased the probability of severe
or life-threatening infection among recipients (Burke,
1992). Burke has concluded that antibody-dependent
enhancement of infection is a general in vitro property
of all enveloped viruses, and that this in vitro activ-
ity is more often than not mirrored by physiological
enhancement of infection as well, particularly when
humoral immunity is not complete.
Particularly frightening in this respect is signifi-
cant data that antibody-dependent enhancement of HIV
infection occurs in vitro and possibly in vivo as well
(reviewed in Burke, 1992). The problem is exacerbat-
ed by the mimicry between HIV proteins and HLA
proteins of lymphocytes that results in immunologic
cross-reactivity between HIV and lymphocyte cellu-
lar receptors (Golding et al., 1988; Vega, Guigo &
Smith, 1990; Garry et ai., 1991; Bjork, 1991; Kion &
Hoffman, 1991; Stott, 1991; Clerici et ai., 1992; Dal-
gliesh etai., 1992; Stisal etai., 1993; Root-Bernstein &
Hobbs, 1991, 1993; Root-Bernstein & DeWitt, 1994).
193
Thus, a recent study of the immunological effects of
recombinant HN gp160 resulted in 3 of 5 human vol-
unteers developing anti-idiotypic antibodies that cross
reacted with their CD4 protein. The study concluded
that such vaccine-induced anti-CD4 antibodies 'poten-
tially may: (1) limit the use of vaccines which elicit
them; (2) contribute to the immunodeficiency occur-
ing in HIV-l-infected individuals, and (3) provide evi-
dence of HIV-l infection during the period when anti-
HN-l antibodies are not detectable, (Keay et ai., 1992;
see also Sabin, 1988).
The presence of non-HIV-induced HIV-like
immune responses in several animal models of AIDS
(Stott, 1991; Kion & Hoffmann, 1991) also raises
the uncomfortable possibility that allogeneic exposure
may confound all tests for AIDS, including T-cell tests.
Salk et ai. (1993) have argued, on the other hand,
that allogeneic exposure might be protective, thus pro-
viding an alternative explanation for why people with
apparent T-cell responses to HN antigens may have
avoided infection (Clerici & Shearer, 1993; Clerici et
ai., 1992).
It follows that presence of HN antibody is symp-
tomatic of a failure of T-cell immunity. The issue in
understanding AIDS now becomes that of establishing
what causes the failure of T-cell mediated immunity.
Since this failure does not occur in a large proportion
of people exposed to HN (e.g., the 15% of severe
hemophiliacs who have not become HN seropositive
and perhaps susbstantially higher percentages of mild
hemophiliacs), it is unlikely that HN is, itself, the
cause of this failure. HIV is more likely an oppor-
tunistic or synergistic infection that becomes manifest
only in people predisposed to or with ongoing causes
of immune suppression, just as cytomegalovirus and
Epstein-Barr virus, which are also extremely highly
correlated with AIDS, remain latent in immunologi-
cally healthy people, but are reactivated to produce
significant viremia and immune suppression in people
whose immune systems are suppressed (see references
below).
Primary T-cell regulation ofHN explains why HN
is such a good marker for AIDS, regardless of whether
it is a causative agent, a synergistic one, or an oppor-
tunistic one. If we assume 1) that reexposure to HIV
is quite frequent among high risk groups; 2) that expo-
sure to variant HN strains is therefore common; 3)
that only those with concomitant and ongoing immune
impairment actually become infected; and 4) that of
those infected, only those with ongoing immunological
stimulation that adversely effects T-cell controlofHN
194
go on to produce antibody; then HIV-seropositivity
becomes a very selective criterion for AIDS risk.
One would expect that whatever processes make an
active HIV infection possible will also activate other
latent viral disease agents. This is, in fact, the case.
Both Epstein-Barr virus and cytomegalovirus reacti-
vation and viremia - not the mere presence of anti-
body - have been reported to be accurate markers
of AIDS progression (Biggar et al., 1983; Drew et
ai., 1985; Fiala et ai., 1986; Rinaldo et al., 1986;
Rahman et al., 1989; Munoz, et ai., 1988; Sumaya et
ai., 1985), and so have diagnostic signs of autoimmune
processes such as the development of lymphocytotoxic
antibodies and circulating immune complexes (Clerici
et al., 1992; Zarling et ai., 1990; Sonnabend, 1989;
Daniel et al., 1989; Ozturk et ai, 1987; Stricker, et
al., 1987a, b; McDougal et ai., 1985). HIV antibody
production and viremia, in other words, are only one
of a very large set of immunologic events that occur
simultaneously in people at high risk for AIDS, and
any or all of these events can trigger the very wide
range of interferon, interleukin, tumor-necrosis-factor,
and other immunological events that are often mis-
takenly attributed solely to HIV (Sonnabend, Witkin
& Portillo, 1984; Sonnabend, 1989; Papadopulos-
Eleopulos, 1988; Root-Bernstein, 1993; Fauci, 1993).
The treatment implications are manifest. By the
time active antibody production against latent virus-
es has begun in people at risk for AIDS, T-cell dis-
regulation is already severe. Those people who sero-
convert immediately following exposure to HIV can
therefore reasonably be conjectured to have been pre-
viously or concurrently immunosuppressed by non-
HIV agents, and I have summarized extremely exten-
sive evidence to this effect elsewhere (Root-Bernstein,
1990a, c, 1992a, b, 1993). For example, progression
to AIDS in hemophiliacs is highly correlated with low
T-cell counts (T-helpers < 500) at the time of infec-
tion, whereas high T-cell counts (T-helpers > 750)
are predictive of very slow progression (Lorenzo et
al., 1993; Sabin et al., 1993). The object of AIDS
prophylaxis mL3t therefore be to prevent the immune
system from decaying to the point that seroconver-
sion becomes possible, or to eliminate ongoing factors
that prevent seroreversion. It follows that antibody-
stimulating vaccines may actually be detrimental.
Alternative approaches for treating HIV-seropositive
people are needed that eliminate ongoing T-cell sup-
pression and rebuild immunity. Some approaches that
embody these principles have apparently been success-
ful, as the next section will outline.
Myth 4: The only way to treat AIDS is to treat HIV
The need for understanding how to treat HIV infec-
tions and AIDS raises the fourth myth that has plagued
AIDS research. For a decade, the paradigm for pre-
venting AIDS has been to treat HIV, since it is believed
that HIV was solely and completely responsible for all
aspects of the pathogenesis of AIDS. It is now well
established that this HIV-centered paradigm has not
yielded any appreciable benefits for AIDS patients and
no miraculous antiretroviral drugs or effective HIV
vaccines are on the medical horizon (Weiss, 1993;
Fauci, 1993). If we accept that AIDS is an immuno-
logical disease (rather than a virological disease) in
which the major disruption occurs in T cells, and if we
accept the fact that different risk groups, and different
individuals within risk groups, progress to AIDS at
different rates due to different cofactor exposures (see
above, Myth #1), and that it is possible for some peo-
ple spontaneously to eliminate HIV (see above, Myth
#2), it becomes manifest that there must be effective
approaches to treating people at risk for AIDS that do
not depend upon targeting HIV We need to identify
and use these non-HIV-centered approaches to AIDS
on the widest possible scale, regardless of whether we
believe that HIV is needed to cause AIDS or not, if
only because we do not have any effective way of con-
trolling HIV directly at present, and have no real hopes
of doing so within the next decade.
One approach that has yielded positive clinical tri-
al results, but little fanfare, is immunologic recon-
stitution utilizing thymomimetic compounds to treat
pre-AIDS patients (reviewed in Hadden, 1991). Got-
tlieb et al. (1991) have reported very good results in
slowing AIDS progression in a multicenter, double-
blind, placebo-controlled trial of the leukocyte-derived
immunomodulator, IMREG-l, and the pharmaceutical
agent has been approved by the U.S. FDA for full-scale
clinical trials. Interest has also been increasing in the
use of non-specific potentiators of delayed-type hyper-
sensitivity (DTH) reactions, such as dinitrochloroben-
zene (DNCB), that have been found to stimulate T-
cell responses, and limited trials suggest some suc-
cess (Mills, 1986; Stricker, Elswood & Abrams, 1991;
Stricker et al., 1993).
A second approach to AIDS is revealed by review-
ing of all known cases of true seroreversion (see ref-
erences in Myth #2 above). Such a review reveals
that none of the seroreverters have been treated with
antiretroviral drugs. Few, if any, of the cases have been

treated for AIDS-associated infections at all. Other fac-
tors seem to be operative.
One factor seems to be limited reexposure to HIY.
Fribourg-Blanc (1988) noted that in the cases of spon-
taneous seroreversion he documented, exposure to
HIV was limited to only one or a few instances. Cer-
tainly exposure was limited (by the death of the sexual
partner) in the case of the hemophiliac wife described
by Burger et al. (1985). Similarly, Farzadegan et al.
(1988) report that seroreversion in their four gay men
followed substantial lifestyle changes that included
switching from mUltiple concurrent and multiple serial
sexual partners to a single, stable sexual relationship,
and rigorous implementation of safer sexual practices.
Personal interviews with three seroreverters who
have provided me with the records of their HIV-
testing have revealed that all underwent significant
lifestyle changes. All three totally eliminated drug use,
began practicing safe sex measures, and went on high-
nutrient diets. These same factors were reported to be
common to all of the long-term AIDS survivors pro-
filed by Michael Callen in his book, Surviving AIDS
(1990) and by anecdotal and self-reporting in The Con-
tinuum Magazine (England), Praxis (U.S.), and other
publications by people with HlY.
Unfortunately, no formal studies of longterm sur-
vi vors of HIV, or of significantly large groups of serore-
verters have yet been carried out, so that it is impossible
to say for certain what factors - genetic susceptibility,
viral variation, viral load and reexposure, immunolog-
ical status and at time of infection, subsequent expo-
sure to cofactor infections or immune impairments
from other sources such as chronic medical treatments,
nutritional determinants - or other factors are respon-
sible for the difference between healthy seroreversion
and fatal development of AIDS. Some clues do exist,
however, in a handful of well-controlled studies.
Substantial data indicating that elimination of one
or more ofthe non-HIV immunosuppressive risks list-
ed above substantially alters the rate of progression to
AIDS in the absence of retroviral treatments. Studies
of HIV-positive intravenous drug abusers show that the
probability of progression to AIDS can be decreased
by a factor of three or more by simply eliminating
ongoing drug use (Groenbladh & Gunne, 1989; Weber
et aI., 1990). Additional treatment for malnutrition and
rigorous practice of safe sex procedures decreases the
rate of HIV progression among IVDUs even further
(Moretti,1992).
Additional evidence for controllable cofactors
in AIDS comes from studies of HIV-seronegative
195
hemophiliacs who display pronounced decreases in
CD4 counts, decreased capacity to produce inter-
leukin II, and immune suppression (Watson & Ludlum,
1992; Hassett et al., 1993; Madhok et al., 1990; Hay,
McEvoy & Duggan-Keen, 1990). This immune sup-
pression has been related to factor VIII therapy (ibid.,
and Farrugia, 1992), active cytomegalovirus and hep-
atitis C infections, and lymphocytotoxic autoantibod-
ies. It is believed that affected hemophiliacs are conse-
quently predisposed to HIV infection and an increased
rate of development of AIDS (Sabin et al., 1993; Gold-
smith et al., 1991; Higgins & Goodall, 1991; Mad-
hok et al., 1991; Schulman, 1991; Webster et al.,
1989; Daniel et al., 1989). Replacing medium puri-
ty blood clotting factor concentrates with high puri-
ty, antibody purified, or recombinant factor that lacks
viral and alloantigenic contaminates for the treatment
of both HIV-seronegative and HIV-infected hemophil-
iacs has resulted in stabilization of T-cell counts, and
in some patients, increasing T-cell counts over sev-
eral years (Hilgartner et aI., 1993; Mannucci et aI.,
1992; Gompert et at., 1992; De Biasi et al., 1991;
Schulman, 1991). Increased T-cell counts are a very
favorable prognosticator of continued health in HIV-
infected hemophiliacs (Daniel et al., 1991).
Another broadly effective approach to AIDS pre-
vention is prophylaxis against cofactor infections. Vac-
cinations that have proven effective in delaying AIDS
onset significantly include Mycobacteria (Kallenius,
Hoffner & Svenson, 1989). Prophylactic treatment of
cofactor infections such as cytomegalovirus and Pneu-
mocystis pneumonia are also associated with decreased
disease progression and also significantly improve sur-
vival among HIV-seropositive individuals (Odell &
Green, 1990; Montaner et al., 1991; Palestine et at.,
1991; Hoover et al., 1993). Such results suggest that
approaches to AIDS prevention that focus on cofactor
prevention, elimination or control may be more effec-
tive than treatment of HIV itself and demonstrate that
HIV alone is not responsible for AIDS. Thus, devel-
opment of vaccines against cytomegalovirus, Epstein-
Barr virus, hepatitis C, and a set of more effective and
less toxic antiviral drugs might be more important for
preventing AIDS than an HlV vaccine, and more wide-
ly applicable in other medical settings (Root-Bernstein,
1992b, 1993).
The evidence that cofactors are necessary to the
progression of AIDS has now convinced a number of
investigators that no comprehensive treatment of AIDS
will be possible without addressing the full range of
cofactors that may influence disease progression. For
196
example, Lafeuillade and Quilichine (1992) argue that
the study of cofactors promises greater 'understanding
of AIDS and hence its therapeutic approach'. Little-
field (1992), in an even stronger statement, says that
it has now become clear that 'one or more supplemen-
tal mechanisms must be involved in the pathogene-
sis of AIDS,' beyond HIV infection per se, and that
'identification of the nature of this [these] supplemen-
tal process[es] has become essential for successful,
nonharmful intervention' .
Since data concerning the role of cofactors as regu-
lators of AIDS are limited, four types of tests need to be
carried out to confirm the observation that elimination
of ongoing immunosuppressive risks (including reex-
posure to mV) is effective in preventing progression
to AIDS. First, large-scale, formal studies of people
exposed to HIV without seroconversion, people who
have seroreverted, and longterm survivors of both HIV
infection and AIDS are desperately needed. Such stud-
ies can conclusively demonstrate whether HIV is suf-
ficient to cause AIDS.
Second, a large-scale formal study is needed
of ongoing immunosuppressive risks among HIV-
seropositive people progressing to AIDS. It is assumed,
but by no means demonstrated, that the immune sup-
pression manifest in such people is due solely to HIV,
but no attempt has been made to investigate ongoing
immunosuppressive exposures.
Third, a study of people exposed to the same
sorts of immunosuppressive agents in the absence
of HIV is mandatory. It is well established that all
risk groups have some degree of immune suppres-
sion independent of exposure to HIV (reviewed in
Root-Bernstein, 1993). No study has ever been carried
out that has examined HIV-positive and HIV-negative
individuals in the same risk groups, paired by ongo-
ing non-HIV immunosuppressive risks. Do all severe
hemophiliacs actively infected with hepatitis B virus,
cytomegalovirus, Epstein-Barr virus, and using inter-
mediate purity clotting factor experience the same T-
cell depletion regardless of HIV infection, or not? To
what degree is their T-cell depletion greater than or less
than uninfected hemophiliacs, or those who use ultra-
pure factor, regardless of HIV status? (That we should
even have to ask for such studies a decade after the dis-
covery of HIV is a symptom of how poorly controlled
and designed research on AIDS has been).
Fourth, a converse study is also necessary that
could potentially prove that HIV is both necessary
and sufficient to cause AIDS: I have challenged the
medical community for four years now to find me a
significant number of people (say 100 or more) with
AIDS who have HIV as their sole immunosuppressive
risk (as defined by the set of clinically recognized fac-
tors known to cause immune suppression that are listed
in my book, Rethinking AIDS [Root-Bernstein, 1993]),
whose T-cell counts and other immunological param-
eters were normal at the time of mv infection, and
who have nonetheless developed T-cell counts below
500 and an opportunistic infection. So far, no one has
responded to this challenge. Surely it is not too much
to ask that a hundred such cases be found among the
hundreds of thousands of AIDS cases that have been
documented, if we are to accept the oft-repeated asser-
tion that HIV alone is sufficient to cause AIDS.
One caveat that must be understood in setting up
the above-mentioned studies is that AIDS itself (as
opposed to HIV infection) may not be reversible. AIDS
may involve slowly progressive processes including
vicious cycles in which multiple sets of infections co-
activate one another, and autoimmune processes that
inexorably cause immune system or other forms of
systemic decay. It may not be possible to reverse AIDS
by simple remediation of risk factors after a certain
point in the disease, as both Sonnabend and I have
pointed out.
We will need, in addition to preventative mea-
sures against AIDS, new, non-retroviral approaches
to disease treatment of multiple, concurrent infec-
tions (many of which are not susceptible to individ-
ual antibiotics), ways to reverse autoimmune process-
es, and methods to reconstitute immune function. The
frightening fact is that very little of this very neces-
sary research has even begun. The HIV paradigm has
blinded most researchers to the undeniable fact that
every AIDS patient (as opposed to HIV-infected per-
son) has one or more autoimmune diseases, and we
do not know how to treat adequately, let alone cure,
any human autoimmune disease; and that every AIDS
patient, even if cured of their HIV infection, would
still have sustained possibly irreversible immunologic
damage. It is entirely possible that we may one day
learn how to vaccinate against or eliminate HIV in
AIDS patients and still have people dying of AIDS-
associated autoimmune conditions and opportunistic
infections simply because we have not yet begun to
investigate the causes or cures of the relevant immuno-
logic processes (Root-Bernstein, 1992a, b, 1993; Root-
Bernstein & Hobbs, 1993).

Myth 5: AIDS must have a single etiologic agent
Another myth that has adversely affected AIDS
research is the assumption, common to much of mod-
em biomedical research, that every disease has a single
etiological agent. As powerful as the one-germJone-
disease/one-cure paradigm has been in the develop-
ment of modem medicine, it has now been admitted
by most HIV experts that the immune system destruc-
tion observed in AIDS cannot be accounted for by
any known mechanism of direct HIV pathogenicity
(Cohen, 1993; Fauci, 1993; Gougeon & Montagnier,
1993; Littlefield, 1992; Lo et al., 1991). Surprising-
ly, this admission has not, however, caused any major
AIDS researchers to question whether HIV is there-
fore sufficient to cause AIDS. There are, however,
other paradigms for disease etiology that are relevant
to AIDS besides the one-germ paradigm that are ful-
ly consistent with existing data, as Sonnabend and
Saadoun pointed out as early as 1984 (Sonnabend &
Saadoun, 1984). Unfortunately, these alternatives are
less well-known than the one-germJone-disease dog-
ma and their implications have been generally ignored
(Root-Bernstein, 1993).
The least revolutionary alternative to the one-germ
paradigm is the two-germ or infectious synergism
paradigm (reviewed in Root-Bernstein, 1993). Perhaps
the earliest proven case of virus-bacterium synergism
was discovered by Shope in 1931, when he showed
that neither Hemophilus injiuenzae nor an unidenti-
fied virus, each of which could be isolated from 100%
of pigs who contracted fatal swine flu, was capable
of causing disease in healthy animals. A combination
of the virus and bacterium, however, nearly always
caused a fatal pneumonia (Shope, 1931). A similar
synergism was found by Dudding et al. (1972) between
adenovirus and several bacteria, including Hemophilus
injiuenzae, which caused fatal pneumonias in man.
Huang and Hong (1973; and Huang et al., 1973)
found that multiple viral infections often resulted in the
production of lymphocytotoxic antibodies in human
patients, accompanied by significant immune suppres-
sion. Hamilton, Overall and Glasgow (1976) found
similarly that combinations of murine cytomegalovirus
with Pseudomonas, Staphylococcus, or Candida infec-
tions were much more likely to be fatal to mice than
individual infections, even when the combined doses
of infectious agents were thousands of times smaller.
Another well-established human example is the com-
bination of influenza virus with Staphylococcus aureus
to yield a severe and often lethal pneumonia (Klenk &
197
Rott, 1988). It is likely that the terrible influenza epi-
demic that killed so many people after World War I
was in fact the result of two or more epidemics (one
influenza, the other(s) unidentified bacteria that over-
lapped.
Significant evidence exists to suggest that HIV may
interact synergistically by mechanisms such as trans-
activation or immunologic cross-reactivity with other
infectious agents associated with AIDS, including her-
pes simplex viruses, cytomegalovirus, Epstein-Barr
virus, H1LV-l, mycoplasmas, and mycobacteria (Lit-
tlefield,1992;Loetal., 1990, 1991; Lusso etal., 1990,
1991; Montagnier et at., 1990; Root-Bernstein, 1990a,
1992a, 1992b, 1993; Wang et at., 1992). All of these
infectious agents are present in people in AIDS risk
groups and in people with AIDS at incidences hun-
dreds of times higher than in the general population
(Buimovici-Klein et at., 1988; Macon et at., 1993;
Root-Bernstein, 1993; Sonnabend, Witkin & Portillo,
1984; Sonnabend, 1989).
A second alternative to the one-germ model is the
multifactorial or predisposition model. HIV may be
an opportunistic agent that, like Pneumocystis carinii
or cytomegalovirus, is not deadly except in immuno-
suppressed individuals. In this case, a broad set of
immunosuppressive agents, including many addictive
drugs, malnutrition, immunosuppressive infectious
agents, and exposure to alloantigens in semen, blood,
blood products, or contaminated needles may interact
to set the stage for active HIV infection (Sonnabend,
Witkin & Portillo, 1984; Sonnabend, 1989; Donohoe
& Falek, 1988; Duesberg, 1990; Fernandez-Cruz et
al., 1988;Papadopulos-Eleopulos, 1988; Pifer et al.,
1987; Root-Bernstein, 1990a, c, 1993).
A third alternative model is an autoimmune mod-
el for AIDS. Virtually all people with AIDS have
lymphocytotoxic antibodies present. Such antibod-
ies are associated with a number of agents, includ-
ing cytomegalovirus infection, exposure to blood and
blood products, and immunologic exposure to semen,
in both HIV and non-HIV infected individuals (Huang
& Hong, 1973; Huang et al., 1973; reviewed in Root-
Bernstein, 1990b, 1992 a, b, 1993; Root-Bernstein &
Hobbs, 1993; Root-Bernstein & DeWitt, 1994; Root-
Bernstein & DeWitt, this volume). Significant debate
surrounds the issue of whether HIV is necessary or
sufficient to induce lymphocytotoxic autoimmune pro-
cesses in AIDS, but significant data point to alloantigen
and infectious agents other than HlV as targets for lym-
phocytotoxic antibodies in AIDS patients, in addition
to HIV (Bjork, 1991; Dalgliesh et al., 1992; Garry et
198
al., 1991; Kion & Hoffman, 1991; Stott, 1991; Ziegler
& Stites, 1986; Sonnabend, 1989; Hoff & Peterson,
1989; Hoff et al., 1991; Zarling et al., 1990; Mor-
row et al., 1991). I, personally, believe that the only
way to explain any autoimmune disease, including the
type that appears in AIDS, is by means of mutiple-
antigen-mediated induction (Root-Bernstein, 1990b,
1991,1993; Root-Bernstein & Hobbs, 1991; 1993).
It is extremely important to realize the statisti-
cal implications of multiple-agent-induced diseases
(MAIDs), whether they are cofactorial, synergistic or
autoimmune, for the epidemiology of such diseases.
Very simply, MAIDs grow at rates that are multiplica-
tive functions of the rate of growth of the individual
agents. If, for example, two synergistic disease agents
are each present in 1 in 1000 people, and the diseases
are randomly distributed, then the probability that they
will coinfect an individual is 1 in a million. Increas-
ing the incidence of each agent by a factor of ten (so
that each is now present in 1 in 100 people) results in
a probability of combined infection of 1 in 10,000. In
other words, a lO-fold increase in the incidence of indi-
vidual disease agents results in a 100-fold-increased
probability of acquiring a combined infection. Increas-
ing the incidence of each agent by a factor of 100 (so
that 1 in 10 people are infected) results in a probabil-
ity of combined infection of 1 in 100, a 1O,000-fold
increased probability of co-infection. Thus, relatively
small increases in the incidence of cooperative agents
lead to extremely large increases in the incidence of the
MAID they cooperati vel y cause. If the two diseases are
co-transmitted, or are transmitted in a non-random way
such as occurs in high risk groups for AIDS, then the
probability of co-infection is obviously increased even
further (Root-Bernstein & Hobbs, 1993). The MAID
theory may therefore explain the observation that peo-
ple in the advanced stages of AIDS seem to be more
of an infectious risk to their partners than are people
with uncomplicated HIV infections (European Study
Group, 1989; Padian, Shibosla & Jewell, 1990): peo-
ple with full-blown AIDS are, by definition, multiply
infected.
The application of the MAID concept to AIDS is
illuminating. One of the most important questions con-
cerning the current epidemic of AIDS is whether HIV is
an old or new virus. A variety of evidence suggests that
both HIV and AIDS have existed in human populations
for decades, and probably for centuries, prior to the
recognition of the first AIDS cases or the discovery of
the virus (reviewed in Root-Bernstein, 1990a, c, 1993).
Why, then, did AIDS become epidemic only during the
1980s? One possibility, for which extensive evidence
exists, is that the modes of transmission grew expo-
nentially during the previous decade as can be verified
by huge increases in all sexually transmitted diseases
and drug use (both intravenous and otherwise) (Dues-
berg, 1992; Root-Bernstein, 1993). But these increased
modes of transmission spread not only HIV, but many
of its putative cofactors - whether they consist of
co-infections, drugs, or exposure to alloantigens or
all three - simultaneously. The simultaneous spread
of HIV and cofactors (consider the co-transmission
of hepatitis viruses and HIV in gay men during the
late 1970s), in this case non-randomly in specific risk
populations, would have resulted in increases sever-
al orders of magnitUde larger in the incidence of any
disease manifestations that are multiple-agent depen-
dent. (Recall, on this point, that the incidence of H1V
seropositive individuals must represent only a frac-
tion of the people actually exposed to HIV -the frac-
tion that did not successfully combat HIV without
developing an antibody response, or who subsequently
seroreverted - see Myth #2 above. Persistently HIV
seropositive individuals therefore probably represent
people who have ongoing cofactor exposure). I have,
in fact, demonstrated that the incidence not only of
HIV, but of active cytomegalovirus and Epstein-Barr
virus infection, hepatitis viruses, Mycoplasma infec-
tions, addictive drug use, lymphocytotoxic antibodies,
and various other immunosuppressive agents is often
hundreds of times higher among high risk group popu-
lations than among low or non-risk heterosexuals and
lesbians (Root-Bernstein, 1993), which would make
the incidence of MAIDs tens of thousands of times
higher among risk groups then in the general popula-
tion. Thus, if AIDS is a MAID, both the time course
of the epidemic, its exponential growth, and its main-
tenance within specific high risk populations can be
explained by the unusual co-incidences of both HIV
and all of its possible cofactors. If, on the other hand,
AIDS is caused solely and simply by HIV, then neither
the timing of the current epidemic nor its specificity
for risk groups is comprehensible.
It should also be noted that a direct consequence
of considering etiologies for AIDS that are more com-
plex than a single agent immediately invalidates two
standard approaches to determining disease causation:
epidemiological correlations and Koch's postulates.
If AIDS is more complex than a simple HIV infec-
tion, then the high correlation between HIV and AIDS
(Koch's first postulate) is not sufficient to demonstrate
that HIV is the causative agent. The observed corre-

lation strongly suggests that HIV is one part of the
cause of AIDS, but it should be expected that other
immunosuppressive agents and/or behaviours will be
as highly correlated with either all AIDS cases, or with
individual risk groups. Thus, it is not surprising to find
that statistically significant correlations exist between
AIDS risk and unprotected receptive anal intercourse
in both men and women (Naz et at., 1990; Adams
et at., 1988; Morrow et at., 1991; Sonnabend, 1989;
reviewed in Root-Bernstein & DeWitt, this volume);
to use of inhalant nitrites by gay men (Vandenbroucke
& Pardoel, 1989; Haverkos, 1988); to general use
of drugs in all risk groups (Duesberg, 1992); and to
the incidence of active infection (not presence of anti-
body) with cytomegalovirus, Epstein-Barr virus, and
mycoplasmas in all risk groups (Buimovici-Klein et
at., 1988; Munoz et at., 1988; Rahman et at., 1989;
Rinaldo et ai., 1992; Lo et at., 1992; Wang et ai.,
1992). But just as HIV is not sufficient to cause AIDS,
so, apparently, are these agents not sufficient to cause
AIDS. Thus, demonstration that people with exposure
to these non-HIV agents do not get AIDS in the absence
of HIV does not prove that they are not part ofthe cause
of AIDS. What must be tested, both epidemiologically
and experimentally, are their combinations. Moreover,
there is no requirement in a multi-factorial disease that
one specific pair of agents be necessary to cause the
disease. One agent may have several different cofac-
tors, none of which correlate highly with the disease.
Or there may be several combinations of agents that
can create the same pathological symptoms (as, for
example, in the case of pneumonia), and therefore no
single agent or set of agents that correlates one hun-
dred percent with all clinically diagnosed cases of the
disease.
What is at issue here are the criteria for evaluating
disease causation. Koch's postulates, focusing as they
do on a single etiologic agent, do not apply to dis-
eases that are caused by multiple, interacting agents.
Thus, the reason why HIV has failed to satisfy Koch's
postulates, despite its obvious presence in virtually all
AIDS cases, may have nothing to do with the oft-cited
species specificity of HIV (an observation belied by the
fact that HIV does infect and replicate in chimpanzee
and macaque lymphocytes) but rather may result from
the fact that Koch's postulates are irrelevant to testing
AIDS etiology (Root-Bernstein, 1992b, 1993). HIV
may not be able to cause AIDS because it is not suffi-
cient to cause AIDS. This is no different than saying
that neither influenza virus or Staphylococcus are suf-
ficient to cause pneumonia. But both are necessary.
199
Diseases such as AIDS that are autoimmune in
nature, or are the result of synergistic or multifacto-
rial processes require the satisfaction of a set of postu-
lates other than Koch's (Witebsky et at., 1957; Root-
Bernstein, 1991). For example, MAIDs may be char-
acterized by satisfying the following criteria: '(1) two
or more infections or immunosuppressive agents will
be active simultaneously in individuals affected with
a particular disease; (2) people with only one of these
agents will either have no symptoms of the disease or
symptoms of another disease that is associated with the
single agent; (3) these multiple agents will be isolatable
or identifiable individually; (4) no single one of these
agents will be capable of inducing the disease by itself
when introduced into healthy human beings or animals
(although they cause different disease symptoms); (5)
an immune response to each agent will be demonstra-
ble during disease induction and will be significantly
altered by the combination of agents as compared with
any agent individually; (6) the disease will be trans-
missible from one animal or human being to another
by means of an appropriate combination of the putative
causative agents. In the case of autoimmune diseases,
the transmissible factors may include tissue or puri-
fied proteins, immune serum, lymphocytes, other cells
or antibodies' (Root-Bernstein, 1993). As far as I am
aware, no one has yet set up an animal model of AIDS
that would satisfy these criteria, and therefore model
AIDS as a MAID. We cannot, therefore, rule out the
possibility that AIDS is caused by some combination
of agents, of which HIV is likely to be one.
The fact is that until someone is able to produce
an animal model of AIDS using the exact set (or sets)
of agents found in human beings (not merely analo-
gous agents such as feline or simian immunodeficien-
cy virus, for example), we will not know whether we
are working with correct or incorrect theories of cau-
sation. My tendency is to believe that having failed
to cause AIDS with HIV alone, we must assume that
AIDS is more complicated than a mere retroviral infec-
tion. On the other hand, the same reasoning makes me
reject Duesberg's suggestion that opiate or other drug
abuse is the cause of AIDS: investigators have worked
with animal models of addiction for decades without
observing AIDS in their animals. Thus, AIDS is more
than just mv or just drugs or just any single agent
that we currently understand. We must now build on
what we know of HIV, but in such a way as to expand
our range of research to look at how it behaves in
the much more complicated conditions that actually
exist in real AIDS patients with multiple infections,
200
blood product exposures, drug exposures, malnutri-
tion, and alloantigen exposure. These conditions have
never been duplicated in animals or test tubes.
On this final point I must insist upon the accuracy
of the following observations. First, there is no docu-
mented case of anyone who has developed AIDS who
does not have several of the following immunosup-
pressive agents at work prior to, concomitant with,
or following their HIV infection: multiple, concurrent
infections with identified immunosuppressive viruses
and bacteria (e.g. herpes viruses, hepatitis viruses, and
mycoplasmas); immunologic exposure to alloantigens
(e.g., semen, blood or lymphocytes); chronic or high
dose treatments with antibiotics; anaesthetics; chron-
ic or high dose use of immunosuppressive addictive
drugs irrespective of mode of use (e.g., heroin); mal-
nutrition; and autoimmunity directed at T-cell subsets
(reviewed in Root-Bernstein, 1990a, c; 1992 a, b;
1993). As a result of these immunosuppressive risks,
many hemophiliacs, blood transfusion patients, drug
abusers, infants of people in these risk groups, and
homosexual men are significantly immuno-suppressed
even in the absence of HIV infection (reviewed in
Duesberg, 1992; Root-Bernstein, 1990a, 1993). Sec-
ond, and conversely, there is no evidence that HIV can
cause disease in an immunologically healthy person
free of these causes of immune suppression: people
with limited exposure to HIV and no ongoing risks of
the sort just enumerated, do not become infected with
HIVor serorevert (see above); and there appear to be no
verifiable tertiary cases of AIDS (i.e., non-risk group
heterosexual to heterosexual transmission) in Western
nations. AIDS is therefore remaining in identified risk
groups (National Research Council, 1993; Fumento,
1990) - a fact that cannot be explained except if pri-
or immune suppression or cofactors are necessary for
HIV transmission and seroconversion.
New directions in AIDS research
The recognition that AIDS may be more complex than
HIV is important because it allows us to re-evaluate
existing data in new ways that reveal both new prob-
lems and new solutions to the epidemic. For exam-
ple, any multiple-agent-induced disease (MAID) can
be eliminated by controlling any of the multiplicity of
necessary agents. Thus, we need not target only HIV
in order to control AIDS, if AIDS can be demonstrated
to be a MAID. Both HIV and its cofactors (see Myth
#4 above) become viable targets for prophylaxis, treat-
ment and cure. Indeed, one of the reasons that current
public health policies such as safer sex, elimination of
drug use, and clean needle exchanges may be working
effectively in many communities (Van Griensven et al.,
1989; Judson, 1990; Winkelstein et al., 1988; Weber
et al., 1990) is that both HIV and many of its cofac-
tors are simultaneously being controlled. According to
the MAID theory, the result of simultaneous control
should be a reduction in new AIDS cases that is a mul-
tiplicative function of HIV and cofactor prevalences.
This possibility mandates a much higher interest in
non-HIV factors associated with AIDS than has thus
far been manifest.
Beyond the obvious point that there are models of
disease causation (and therefore prevention and treat-
ment) that have been ignored by the majority of AIDS
researchers lies an even more important point: scien-
tific research consists of elaborating all of the possible
explanations of a phenomenon and then eliminating,
through controlled observation and experiment, all but
one of these (Root-Bernstein, 1989). Because this is
the way all good science works, philosophers and prac-
titioners of science both agree that one can never prove
that the remaining answer is true; one can only prove
that all of the other possibilities are not (Popper, 1962;
Medawar, 1967). (Anyone who remembers learning
Mendelian genetics will recall that the key to solv-
ing genetics problems is not determining what type of
inheritance explains any particular cross, but remem-
bering all of the different possibilities and searching
for the crucial evidence that makes all but one of them
untenable). Good scientific research therefore consists
primarily of performing experiments that disprove the-
ories, rather than gathering data that purport to support
a preconceived notion.
In pointing out that too much AIDS research has
been directed by myths that have been accepted uncrit-
ically by the majority of investigators, and that sever-
al well-established models of disease causation have
been ignored as well, I am therefore arguing that AIDS
research as a whole has not followed standard sci-
entific practice of skeptical elaboration of possibilities
followed by disproof. Instead, the community of AIDS
researchers has reversed standard practice by leaping
to the conclusion that the first obvious answer (HIV)
must also be the best and the most correct answer. Until
it can be demonstrated that no other possible expla-
nation of AIDS exists besides HIV alone, and until
specific tests are performed to attempt to disprove the
HIV theory, there is no methodological justification for

limiting research to HIV alone. This is basic scientific
method.
Einstein had some advice to scientists. He said that
when devising a theory, make it as simple as possi-
ble and no simpler. My view of AIDS research, which
owes a great deal to the pioneering work of Joseph
Sonnabend, is that both those who study HIV and
those who refuse to acknowledge its role in AIDS have
oversimplified. AIDS is complex. AIDS is multifacto-
rial, and the diverse factors that are correlated with the
various risk groups for AIDS all interact synergistical-
ly. Until we understand these interactions in their full
complexity and set up appropriate experiments to test
whether any of them are relevant to AIDS pathogene-
sis, we will continue to act, as we act today, like the
blind men describing the elephant, each attributing all
of AIDS to the part of the thing with which we are
in closest contact (Root-Bernstein, 1993). Meanwhile,
people with AIDS die as a result of our blindness.
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Semen alloantigens and lymphocytotoxic antibodies in AIDS and ICL

Robert S. Root-Bernstein 1 & Sheila Hobbs DeWitt2

1Department of Physiology, Michigan State University, East Lansing, M148824, USA
2Parke-Davis Pharmaceutical Research Division, 2800 Plymouth Road, Ann Arbor, MI 48106- I 047, USA

Received 27 January 1994; Accepted 17 June 1994

Key words: AIDS, a\loantigen, autoimmunity, lymphocytotoxic antibodies, semen

Abstract

More than 90% of people with AIDS develop circulating immune complexes (CICs) and lymphocytotoxic antibodies
(LCTAs). Animals infected with HIV, however, never display CICs or LCTAs, and remain healthy. Similarly, HIV-
infected people who do not develop CICs or LCTAs also do not progress to AIDS. The appearance of CICs
and LCTAs is, however, highly prognostic for AIDS and death. Since HIV infection does not, per se, lead to
the development of CICs and LCTAs, other causes are likely. One such cause, for which both epidemiologic
and experimental evidence exists, is semen. Semen components include sperm, seminal fluid, lymphocytes,
and sometimes infectious agents, including HIV, mycoplasmas, and herpes and hepatitis viruses, all of which
independently cause immune suppression. Extensive evidence demonstrates sperm (and various viruses) contains
many proteins mimicking the CD4 protein ofT-helper cells, while HIV, mycoplasmas, and seminal fluid mimic class
II MHC proteins of other lymphocytes. We identify a large number of protein sequences that display such mimicry
using computer homology searching, and demonstrate experimentally that sperm antibodies specifically precipitate
antibodies against class II MHC mimics such as mycoplasmas, which in turn precipitate antibodies to lymphocyte
antigens. These data prove that immunologic exposure to sperm and lymphocytes (as may occur in receptive
anal intercourse, needle sharing, or blood transfusions) is theoretically capable of initiating lymphocytotoxic
autoimmunity. Such autoimmunity may playa significant role in the pathogenesis of AIDS, and will need to be
addressed clinically in high risk individuals regardless of HIV status and regardless of the success of anti-HIV
prophylaxis and treatment.

Introduction Lori & Gallo, 1990; Lo et al., 1991; Duesberg, 1990,

AIDS and ICL are due to more than just HIV
An increasing body of evidence suggests that human
immunodeficiency virus (HIV) may not be a suffi-
cient, or in some cases (many now classified as idio-
p&thic CD4-T-cell lymphopenia or ICL) even a neces-
sary, cause of acquired immune deficiency syndrome
(AIDS). Various co-factors, including other retrovirus-
es, mycoplasmas, herpes viruses, and drugs have been
postulated to act as either necessary co-factors or as
adjuvants for HIV infections (Sonnabend & Witkin,
1984; Sonnabend, 1989; Holmberg et al., 1988; Lusso
et al., 1988; Buimovici-Klein et al., 1988; Montagnier
et aI., 1990; Root-Bernstein, 1990a, 1990c, 1992a,
1992b; Squinto et aI., 1990; Haverkos, 1990; Lusso,
1992; Littlefield, 1992). Moreover, increasing interest
is being expressed by AIDS researchers in the possi-
bility that autoimmunity may playa significant role in
T-cell depletion (Sonnabend & Witkin, 1984; Andrieu,
Even & Venet, 1986; Ziegler & Stites, 1986; Golding et
al., 1988; Hoffmann & Grant, 1989; Hoffmann, 1990;
Littlefield, 1992; Sonnabend, 1989; Morrow et al.,
1991 ; Root-Bernstein, 1993; Root-Bernstein & Hobbs,
1993; Weiss, 1993; Fauci, 1993). Particularly note-
worthy are reports of lymphocytotoxic autoantibodies
directed at CD4+ T cells in up to 95% of AIDS and
60% of AIDS related complex (ARC) patients but not
in healthy HIV-infected people or HIV-infected chim-
panzees and macaques. (Dorsett et al., 1985; Kiprov
et aI., 1985; Kloster, Tomar & Spira, 1984; Strickler
208
et at., 1987a, 1987b; Kopelman & Zolla-pazner, 1988;
Zarling et at., 1990; Szabo et at., 1992; Stroncek et at.,
1992; Clerici et at., 1993).
Whether lymphocytotoxic antibodies are a cause of
AIDS, a pathogenic correlate to AIDS development,
or simply one of the many disease manifestations that
accompanies immunological breakdown as a result of
AIDS is not, at this time, known. Regardless of the
role such autoimmune processes play in AIDS, how-
ever, it is clear that they, like all autoimmune phe-
nomena, progress independently of their initiating fac-
tors and therefore represent a problem of significant
clinical concern. The problem of autoimmune phe-
nomena in AIDS is exacerbated by two factors: the
complete ignorance of the biomedical research com-
munity concerning the cause or causes of any human
autoimmune diseases or their effective treatments and
the probability that such phenomena will continue to
affect AIDS patients regardless of the success or fail-
ure of anti-retroviral therapies and prophylaxis. We
therefore believe that it is essential that the causes of
autoimmune phenomena in AIDS be elucidated and
animal models of them developed so that the critical
work of finding preventative and curative procedures
can have some hope of success.
One among many antigenic stimuli that might act
as a possible cause of autoimmunity and co-factor in
AIDS pathogenesis are alloantigens found in blood and
semen (Hsia et at., 1984; Shearer & Rabson, 1984;
Hoff & Peterson, 1989; Hoff et at., 1991; Kion &
Hoffmann, 1991; Stott et at., 1991). All groups iden-
tified as being at high risk for AIDS are characterized
by having repeated immunologic exposure to foreign
lymphocytes or their proteins (through exposure to
blood or blood products) or to semen (which contains
both sperm and lymphocytes). Both Stott et al. (1991)
and Kion and Hoffmann (1991) have demonstrated
the presence of anti-lymphocyte antibodies that cross-
react with HIV antigens in HIV-free animals exposed
to lymphocytes or with autoimmune diseases such as
lUpus. Indeed, lymphocytes are common components
of both blood and semen (Shearer & Rabson, 1984),
and strong evidence has existed from the outset that
semen components (sperm and/or lymphocytes) may
playa pathogenic role in AIDS. Receptive anal inter-
course is the most significant of the risks identified for
homosexual and bisexual men (Darrow et at., 1987)
and for heterosexual women (The European Study
Group, 1989; Padian et at., 1990). The same mech-
anisms proposed for promoting HIV and other sexu-
ally transmitted infections - abrogation of the anal or
intestinal tissue due to unprotected anal forms of sex
or untreated sexually transmitted or enteric diseases -
would also permit sperm cells and foreign lymphocytes
to enter the blood stream or lymph system.
Although women who practice anal intercourse and
subsequently develop AIDS have not specifically been
tested for LCTAs and anti-serum antibodies, nearly
all i.v. drug addicts regardless of sex, are positive for
anti-MHC antibodies (de la Barrera et at., 1987), and
30% of unselected female AIDS patients in one New
York study (that included many i.v. drug abusers) had
significantly high antibody to human sperm extract,
protamine, and fertilization antigen as compared with
healthy controls (Naz et at., 1990). The prevalence of
such antibodies in male homosexual AIDS patients is
much higher: 40% have significant antibody against
human sperm extract, 70% against protamine, and
70% against fertilization antigen (Naz et at., 1990).
Such antibodies were not present in any HIV-negative
individual tested. The presence of circulating immune
complexes (CICs) which included anti-semen antibody
components was even higher in each group. CICs were
found in 90% of male AIDS serum samples and 80%
of female AIDS serum samples (Naz et at., 1990).
These figures have been verified by other investiga-
tors looking at autoimmune problems associated with
. AIDS (see autoimmunity references above and anti-
sperm antibody references below). The importance of
CICs is that they represent sure diagnostic signs of
autoimmune phenomena.
The presence of anti-lymphocyte and anti-semen
antibodies is of great potential importance for under-
standing AIDS. Autoimmune processes in AIDS are
directed at virtually every organ, system, and tissue
in the body (Morrow et at., 1991). Obviously, anti-
lymphocyte antibodies may playa significant role in
immune suppression, not only against T-helper cells,
but other cells in the immune system as well. More-
over, sperm contains a large number of antigens that
are cross-reactive with other human tissues, includ-
ing lymphocytes, kidney and brain (Lewis, 1934; Naz,
1988), and may therefore induce a range of autoim-
mune disease symptoms. Among these autoimmune
effects are T-cell suppression, since anti-sperm anti-
bodies have been demonstrated to cross-react with host
T-cells in AIDS risk groups, and to be a direct cause
of immunosuppression through T-cell killing (in vitro)
(Adams et at., 1988; Bagasra et at., 1988; James &
Hargreave, 1984; Mathur et at., 1981; Mavligit et at.,
1984; Rubenstein et at., 1989; Witkin & Sonnabend,
1983). Indeed, lymphocytotoxic antibodies have been

found not only in HIV-positive, but in some high-risk
HIV-negative homosexuals; however, such antibodies
are not found in healthy heterosexual controls (Kiprov
et at., 1985; Adams et at., 1988).
Anti -sperm antibodies may also be the cause of the
anti-testicular and nervous system autoimmunity that is
present in virtually all gay men and many women who
develop AIDS. Aspermatogenesis, sperm maturation
arrest, and testicular fibrosis are the rule rather than
the exception in such patients (Reichert et at., 1983;
Welch et at., 1984; Niedt & Schinella, 1985; Krieger et
at., 1991). Autoimmunity directed at brain proteins is
also extremely common, if not universal among AIDS
patientsjMorrow et at., 1991), and interestingly the
connection between sperm LCTAs and brain antigens
has been verified by studies of people who develop
LCTAs following spinal cord damage; these LCTAs
cross-react with sperm, and can cause aspermatogen-
esis (Hirsch et at., 1992; Tsatsoulis & Shalet, 1991).
Thus, anti-sperm immunity can result in a wide range
of immunologically-based pathologies associated with
AIDS.
Experiments in animals have confirmed that
immunological exposure to semen, including anal
modes of presentation, can result in T-cell immuno-
suppression as measured by T-cell counts and activ-
ity assays (Hurtenbach & Shearer, 1982; Richards,
Bedford & Witkin, 1983). These animals were not
exposed to opportunistic infectious agents, so it is not
known whether their immune suppression was signif-
icant enough to result in AIDS, or merely represents
a predisposing factor or cofactor for AIDS develop-
ment. Similar experiments have shown that seminal
plasma also contains proteins that directly inhibit T-
cell blast transformation, natural killer (NK) cell and
macrophage activity, and response to foreign antigens.
(Lord, Sensabaugh & Stites, 1977; Anderson & Tarter,
1982; James et at., 1983; Williamson, 1984; Schopf et
at., 1984; Erikson, 1984; Marcus et at., 1987; Quayle
et at., 1987; Naz et at., 1990).
Most importantly for the possible role semen may
play as an inducer of lymphocytotoxic autoimmuni-
ty in AIDS and ICL, sperm contains proteins that
immunologically mimic lymphocyte proteins (Naz,
1988). Gobert et at. (1990) have demonstrated that
anti-CD4 monoclonal antibodies react with several dif-
ferent proteins in sperm membranes, sperm extract,
and seminal fluid, and significant regions of homology
between CD4 protein and sperm surface proteins have
'been reported (Root-Bernstein & Hobbs, 1993). Ashi-
da and Schofield (1987) have shown that sperm will
209
therefore bind to class II MHC receptors on lympho-
cytes. Conversely, Bagasra et at. (1988) have demon-
strated that HIV (which mimics class II MHC activity
by binding to CD4 receptors on T cells) will bind to the
CD4-like epitopes on sperm. Interestingly, Mycoplas-
mas, which share large homologous regions of class II
MHC-like sequences with HIV gp120 protein (Root-
Bernstein & Hobbs, 1991, 1993), also bind to sperm
(Black, 1983). Thus, it is likely that many immuno-
genic agents associated with AIDS 'piggyback' on
each other, so that sperm, HIV, Mycoplasmas, and
other disease agents associated with AIDS may all be
transmitted as complexes that act synergistically when
immunologically processed (Root-Bernstein & Hobbs,
1993). Additionally, Autiero, Abrescia and Guardiola
(1991) have discovered class II MHC-like seminal pro-
teins that bind directly to CD4-like sperm proteins, and
which may therefore themselves mimic the antigenic-
ity of both class II MHC lymphocytes and HIV gp120
protein. Since anti-CD4 antibodies and anti-HLA anti-
bodies are both extremely common forms of LCTAs
in AIDS patients (Shearer & Rabson, 1984; Shearer,
1984; Sonnabend, 1989; Morrow et at., 1991), these
data concerning the antigenic similarities and cross-
reactivities of semen components with lymphocytes
are striking clues as to the possible causes of at least
some of the lymphocytotoxic autoimmunity found in
AIDS and ICL.
Theory
The rote of homotogies in the induction of
autoimmunity
Given these facts, we surmised that proteins found
in sperm might induce lymphocytotoxic autoantibod-
ies, and therefore that significant homologies might
exist between semen proteins and proteins of lym-
phocytes including but not limited to CD4. Simple
homology between self and nonself proteins, combined
with exposure to the nonself protein, is not, however,
sufficient to induce autoimmunity (Westall & Root-
Bernstein, 1983, 1986; Root-Bernstein, 1991).
The basic phenomenon of autoimmunity is that the
immune system, which normally protects the body
from disease, turns upon the body itself in a sort of
immunologic civil war. The response can be medi-
ated by B cells or T cells, or both. In most cases,
the resulting immunological civil war develops over
many years (as, notably, I does AIDS), and is
210
progressively debilitating. Well-known, slowly pro-
gressing, often fatal examples of autoimmune diseases
are multiple sclerosis, systemic lupus erythematosis,
and amyotrophic lateral sclerosis, For reasons that
are not understood, the part of the immune system
that distinguishes between self and non-self fails, and
the immune system targets its own tissues or organs
for destruction. One reason that no one understands
autoimmunity is that no one has yet put forward a
cogent theory of how the immune system distinguish-
es between self and non-self. One thing all theories
of autoimmunity agree upon is that self-nonself dis-
tinction is partially lost during autoimmunity, and that
mimicry between the inducing agent or agents and self
tissues is at the root of the failure of the immune system
to distinguish between self and non-self (reviewed in
Root-Bernstein, 1991).
There are three basic types of theories about how
autoimmune processes are initiated (reviewed in Root-
Bernstein, 1991). The first type can generally be called
the 'antigenic mimicry' theory (Fujinami & Oldstone,
1985; Oldstone, 1987; Bjork, 1991; Susal etal., 1993).
According to this type of theory, infectious agents may
contain proteins that sequentially or structurally mim-
ic proteins within the host body. Under normal cir-
cumstances, these antigenic mimics will not provoke
an immune response from the host because the host
immune system 'recognizes' that to do so would result
in an autoimmune reaction as well. Under some con-
ditions (which are never specified in these theories),
the self/non-self distinction is abrogated. It is gener-
ally asserted that this loss of self/non-self distinction
occurs most often if the antigen is different enough
from the host protein to elicit an immune response, but
similar enough to allow functional cross-reactivity. In
AIDS, a relevant example is the well-established anti-
genic and functional mimicry ofHIV gp 160 with MHC
class II proteins (Bjork, 1991; Dalgleish et al., 1992;
Susal et al., 1993). Alloantigens are another source of
antigenic mimics.
A second type of autoimmune theory proposes that
the cause is no' the primary response to an antigen,
but the anti-idiotype response (Plotz, 1983; Williams
et al., 1989; Hoffmann & Grant, 1989). Typical-
ly, the immune system mounts a primary antibody
response against an antigen. When the antigen is elim-
inated from the host, a secondary immune response is
elicited in which the primary, or idiotypic antibody,
induces a chemically complementary antibody, known
as the anti-idiotype antibody. According to Ierne's
network theory of immunologic control, as series of
such idiotype/anti-idiotype networks is what regulates
immune function. In order to induce autoimmuni-
ty, anti-idiotype theories suggest that the following
sequence of events occurs. A virus (or other infectious
agent) uses a host cellular receptor to enter a cell. The
viral coat proteins are chemically complementary to
this cellular receptor. (An example relevant to AIDS
would be the use of gp160 binding to CD4 receptors
to infect macrophages, dendritic cells, and T-helper
cells.) According to the anti-idiotypic autoimmunity
theory, the primary antibody response will be to the
foreign antigen gp160. This idiotypic antibody will
have the same general specificity as CD4. The idio-
typic antibody will, in turn, induce an anti-idiotypic
antibody which will now mimic the binding properties
ofthe original antigen, gp160. Thus, this anti-idiotypic
antibody will recognize as its target, the same cellu-
lar receptor as its target, as does the virus (Hoffmann
& Grant, 1989). In this way, viruses might be able
to induce autoimmune processes against their target
tissues. Similarly, anti-CD4 autoimmunity might be
provoked by alloantigenic exposure to MHC class II
proteins following exposure to blood or semen (Kion
& Hoffmann, 1991; Stott et al., 1991).
A number of important difficulties exist with both
the antigenic mimicry and anti-idiotype theories of
autoimmunity. First, neither specifies how or under
what circumstances the self/non-self distinction will
be abrogated. Indeed, the anti-idiotype theory asserts
that the very network of idiotype/anti-idiotype inter-
actions that is supposed to regulate immune func-
tion is the cause of autoimmunity! Second, molecular
mimicry, although undoubtedly necessary to induce a
cross-reactive autoimmune response, cannot be suf-
ficient. More than 3% of monoclonal virus antibod-
ies have been found to cross-react with human tissues
(Srinivasappa et al., 1986), and we are infected with
hundreds of viruses during our lifetimes. If simple
antigenic mimicry, whether idiotypic or anti-idiotypic,
were sufficient to induce autoimmunity, we should all
end up with multiple autoimmune diseases following
every viral infection. The actual incidence of any indi-
vidual autoimmune disease is on the order of one in
tens or hundreds of thousands and the cumulative inci-
dence only a few percent of the population, even if we
include the arthritic diseases. Thus, something medi-
ates between the commonness of antigenic mimicry
and the rarity of autoimmunity. Finally, simple expo-
sure to purified alloantigens and molecular mimics
does not lead to autoimmunity in experimental and nat-
ural conditions (reviewed in Root-Bernstein, 1991). If

it were otherwise, vasectomies or uncomplicated vagi-
nal intercourse would each carry a significant risk of
the development of anti-semen antibodies that could
induce autoimmune conditions. As far as is known,
they do not. For example, LCTAs do not result in
human beings from true auto-exposure to sperm, such
as that following vasectomy (Jennings, Wettlaufer &
Paulsen, 1977).
A third theory of autoimmunity has therefore
been proposed that satisfies all known data from
animal experimentation, explains how the self/non-
self distinction is abrogated, and accounts-for the
extreme rarity of autoimmune processes in the gen-
eral population while also explaining why it is so
high among people with AIDS. This third theory
is called the multiple-antigen-mediated autoimmuni-
ty (MAMA) theory (Westall & Root-Bernstein, 1984,
1986; Root-Bernstein, 1990b, 1991, 1993). It sug-
gests that autoimmunity is due to more than simple
cross-reactivity following antigenic processing of self-
mimicing antigens. Such self-mimicry is a necessary,
but insufficient condition for inducing autoimmunity
according to MAMA. MAMA requires a pair of anti-
gens which are chemically complementary, at least
one of which is a self-mimic. It therefore predicts that
autoimmunity is most likely to occur in people infected
with or exposed to multiple, concurrent allogeneic or
infectious antigens.
MAMA was proposed in 1984 by Westall and
Root-Bernstein (1984, 1986) to explain animal
models of multiple sclerosis (experimental allergic
encephalomyelitis), experimental autoimmune orchi-
tis, and experimental thyroiditis. In each of these
experimental autoimmune diseases, two chemically
complementary antigens (Root-Bernstein & Westall,
1990) are necessary to induce the disease. Neither anti-
gen can induce autoimmunity by itself. Each antigen
induces an antibody (or T-cell) response specific to
it. Since the antigens are chemically complementary,
some of the respective antibodies or T-cells are also
complementary - or in immunological terms, they are
idiotype/anti-idiotypepairs (Fig. 1). Each antibody (or
T-cell) now recognizes the other as mimicing an anti-
gen. Self/non-self distinction is therefore abrogated by
the simple act of producing an immune response to
each antigen. If one or both of the antigens also mim-
ics a self-protein, then part of the immunological civil
war that results will be directed at a tissue target as
well (Westall & Root-Bernstein, 1983, 1986).
There is an additional constraint imposed on the
induction of autoimmunity by the MAMA mechanism,
211
•
"Sail"
CD4
Fig. 1. The immuuologically disruptive effects of processing
two, chemically complementary antigens (Agi and Ag2) that mim-
ic the complementary lymphocyte proteins CD4 and class II MHC
(HLA class II). The resulting antibodies (Ab I and Ab2) are chem-
ically complementary to their antigens, but are also chemical-
ly complementary to each other, therefore representing an idio-
type/anti-idiotype pair (though each is truly an idiotypic antibody).
As a result of molecular mimicry, self and non-self antigens become
confused (CD4, AgI, and Ab2 are all mimics, as are class II MHC,
Ag2, and Ab I). Inability to distinguish self from non-self results,
allowing the immune system to attack the body; disregulation of the
idiotype/anti-idiotype system results, so that the autoimmune pro-
cess is unregulated, and circulating immune complexes made up of
Ab I, Ab2, Agl and Ag2 are formed.
which is also bolstered by extensive experimental evi-
dence. As noted above, the antigenic stimuli must be
present concurrently. It has been shown both theoreti-
cally and experimentally that if one of the pair of com-
plementary antigens is present significantly prior to the
other, so that a full immune response is in place prior to
exposure to the second antigen, then no autoimmunity
will be induced. On the contrary, it has been exten-
sively demonstrated that any individual antigen from
a pair can vaccinate against the autoimmunity induced
by the corresponding antigen pair (reviewed in Westall
& Root-Bernstein, 1984, 1986; Root-Bernstein, 1991).
We emphasize that the outcome of the MAMA
theory is virtually identical to an idiotype/anti-
idiotype theory of autoimmunity proposed previous-
ly by Hoffmann to explain AIDS-associated autoim-
munity (Hoffmann & Grant, 1989; Hoffmann, 1991).
The major difference between the theories is that
MAMA requires two chemically complementary anti-
genic inducers, whereas Hoffmann believes that a sin-
gle antigen can induce autoimmunity through the sim-
ple anti-idiotype mechanism described above. (See
Root-Bernstein, 1991 and 1993 for a more detailed
explanation for why we do not believe that Hoffmann's
theory is tenable.)
Epidemiologic evidence supports the MAMA the-
ory. According to the MAMA theory, the reason
autoimmune conditions are thousands of times more
212
common in AIDS patients than in the general popula-
tion (reviewed in Marrow et at. 1991) is that people
with AIDS have an extremely high incidence of multi-
ple, concurrent infections combined with alloantigenic
stimuli (Root-Bernstein, 1991, 1993; Root-Bernstein
& Hobbs, 1993). We believe that specific combina-
tions of antigens are necessary to induce the vari-
ous autoimmune diseases associated with AIDS and
have previously demonstrated that a combination of
active herpes virus infection with a mycobacterial
infection is extremely high correlated (p > 0.01) with
the incidence of autoimmune demyelinating disease in
both AIDS and non-AIDS patients (Root-Bernstein,
1990b).
The application of the MAMA theory of T-cell
directed autoimmunity to AIDS is similarly com-
pelling (Root-Bernstein, 1991, 1993; Root-Bernstein
& Hobbs, 1993). The major targets of autoimmunity in
AIDS are T-helper cells and class II MHC. These cells
are known to have chemically complementary proteins
on their cell surfaces: the CD4 protein of T-helper
cells and macrophages, and the class II MHC proteins
on HLA-bearing cells. The interaction of these two
molecules in the presence of antigen is necessary to ini-
tiate immune responses. We have summarized above
significant data showing that various components of
semen, including sperm itself, seminal fluid, and lym-
phocytes contain CD4-like antigenic sequences. All
that is necessary to satisfy the conditions for inducing
autoimmunity set out by our hypothesis is that sperm
be presented to the immune system at the same time as
class II MHC-like antigens, and evidence summarized
above demonstrates that these are also often present
in semen in the form of HIV antigens (gpI20) and
mycoplasma infections, and possibly class II MHC-
bearing lymphocytes. Thus, it is very likely that the
semen of people with AIDS will, unlike the semen of
the vast majority of the male population, contain both
CD4 and class II MHC-like antigens that may be suffi-
cient to induce autoimmunity directed at lymphocytes
bearing both sorts of proteins in anyone immunologi-
cally exposed to their semen.
Before going further, we must stress the point
that autoimmunity will result only from immunolog-
ic exposure to the semen-infection combination. Anti-
genic exposure to semen during vaginal intercourse is
extremely rare because there are no lymph nodes in the
immediate vicinity, few lymphocytes within the vagi-
na or cervix, and no access to the blood stream during
the normal course of events. Thus, antibody respons-
es to semen components in women without AIDS are
extremely rare, and of these responses almost none are
of the lymphocytotoxic type, but are rather directed at
non-mimicry regions of semen. Furthermore, even if
semen were to acquire access to the blood or lymph sys-
tem, we reiterate that it would provoke an autoimmune
response only if it were immunologically processed
with an appropriate antigenic cofactor (allogeneic or
infectious).
One prediction unique to the MAMA theory is eas-
ily testable and positive results would help to estab-
lish its plausibility (although it certainly will not prove
it). The theory uniquely predicts that since one anti-
gen mimics CD4 (or a similar T-cell antigen) and
the other antigen mimics class II MHC (or a simi-
lar lymphocyte antigen), then the antibodies against
this pair of antigens should be chemically comple-
mentary. In other words, the two separate antigens
should induce idiotypelanti-idiotype antibody pairs.
These idiotypelanti-idiotype antibody pairs (actually
two interacting idiotypes) will precipitate each other.
Furthermore, the theory requires that one or both of
these antibodies be capable of cross-reacting with a
self antigen. This cross-reactivity will also be evident
as precipitation of antibody raised to this cross-reactive
antigen, due to complementarity. The result will be the
in vitro equivalent of the circulating immune com-
plexes (CICs) that typify the autoimmune processes
present in nearly all AIDS patients (see above and Fig.
1). Since the inducing antigens mimic both CD4 and
class II MHC proteins, the loss of self/non-self distinc-
tion will allow the immune response to the antigens
to become autoimmune in nature. In this instance,
the resulting immunologic civil war will be directed
against CD4 and class II MHC lymphocytes, resulting
in T-cell loss and non-specific immunologic activa-
tion (Fig. 2). No other theory of autoimmunity pre-
dicts these sorts of idiotypelanti-idiotype interactions
(with the possible exception of the Hoffmann theory),
and therefore evidence of the type of mutual antibody
precipitation predicted here will uniquely support the
MAMA theory.
Methods
Protein similarity searches
In order to test the plausibility of semen as a plausible
inducer of autoimmunity, we performed two types of
studies. The first involved computer-based searches for
protein similarities between semen-associated proteins

~
A2.
g
CD4 +
cell
Aaif-
cell
Fig. 2. As a result of the process begun in Fig. I, Abl
can attack Agi and its self mimic, CD4; Ab2 can attack Ag2
and its self mimic, class II MHC; and immune complexes can
form between CD4 and class II MHC cells, causing syncitia.
In addition, circulating immune. complexes will form complexes
between CD4 proteins and Ag2, as well as between class II MHC
and Agl. These antigen-lymphocyte-receptor complexes and anti-
body-lymphocyte-receptor complexes would result in non-specific
activation of immunity, as is universally observed in AIDS.
and lymphocyte proteins. Positive evidence of protein
sequence similarities between sperm and lymphocyte
antigens and cellular targets of autoimmunity in AIDS
would support the plausibility of molecular mimicry
being the basis of autoimmune reactions in AIDS. It
would not, however, distinguish between autoimmune
theories. The second test is therefore specifically to dif-
ferentiate the MAMA theory from other autoimmune
theories. It consists of a preliminary screen of antibod-
ies against sperm, lymphocytes and infectious agents
found in the semen of AIDS patients that might inter-
act in the complementary manner proposed above to
produce an in vitro model of CICs.
We performed homology searches utilizing two
methods available in the Genetics Computer Group
Sequence Analysis Software package (Devereux, Hae-
berli & Smithies, 1984). A Wilbur and Lipman
(1983) style WORDSEARCH of the Swiss-Prot Pro-
tein Sequence Database (18,364 proteins) was accom-
plished using a word size of 4 (4-mer) with no mis-
matches and a word size of 5 (5-mer) allowing one
mismatch followed by alignment of the 400 best diag-
onals of each of these analyses. Additionally, a Pear-
son and Lipman (1988) FASTA analysis of the Swiss-
Prot Protein Sequence Database using a word size
of 2 (2-mer) followed by alignment of the 400 best
213
diagonals was also performed. The resulting printouts
were then analyzed in light of their potential relevance
for the hypothesis under consideration. Homologies
were screened for significance using the following cri-
teria: an identical amino acid was given a score of
one; acceptable substitutions were given a score of
one half; a homology was considered significant only
if a sequence achieved a score of at least five with-
in a sequence of ten amino acids (i.e., at least a 50%
identity in a lO-mer). lO-mers were chosen as rea-
sonable lengths for evaluation since peptides of this
length are more or less what are recognized by T-cell
receptors (Rudensky et at., 1991). In fact, the report-
ed sequences, in general, are greater than ten amino
acids in length and achieve much higher degrees of
similarity than we required.
Controls were run to determine the degree to which
random matches between proteins might occur. Where-
as six similar sequences between CD4 and sperm pro-
teins appeared in the 400 best fits when the CD4
sequence was run against the entire Swiss-Prot data
base, no similarities were found among the top 400 best
fits when CD8, human serum albumin, nerve growth
factor, or the three T-cell receptor subunits (alpha, beta,
and gamma) were run against the data base. We there-
fore interpret these negative data to mean that the sim-
ilarities we are reporting between CD4 and sperm pro-
teins are significantly unusual.
We make no claim to completeness. Significant
homologies may exist between lymphocyte proteins
and semen proteins other than the ones we report here,
particularly as the protein sequence data base is con-
tinuously growing. Due to the strict bias employed in
evaluating the data, the large amount of corroborative
data achieved by these methods, and due to previous
work that has found a very large number of additional
similarities specifically between lymphocyte proteins
and cell sUiface proteins of sperm that are not reported
here (Root-Bernstein & Hobbs, 1993), no additional
searches were pursued. Only similarities not published
previously are listed in the present paper.
Immunodiffusion studies
The specific predictions of the MAMA theory regard-
ing coprecipitation of complementary antibodies to
pairs of complementary antigens (Fig. 1) was tested
using a modification of standard Ouchterlony immun-
odiffusion (Ouchterlony, 1968), in which antibody is
diffused through an agarose gel against other antibod-
ies instead of against antigens. We term this modified
214
technique double antibody diffusion, or DAD (Root-
Bernstein, 1994).
We obtained immune serum (sheep) raised against
human sperm from two suppliers (Chemicon; Arnel)
and seventy-five polyclonal (PAB) and monoclonal
(MAB) antibodies against human lymphocyte proteins,
bacteria, and viruses associated with AIDS. These
antibodies included 14 mycoplasmas, 4 mycobacte-
ria, 2 Streptococci, I Staphylococcus, I E. coli, 2
Candida albicans, 8 HIV, 8 cytomegalovirus (CMV),
3 hepatitis B virus (HBV), 3 herpes simplex virus
(HSV), 4 Epstein-Barr virus (EBV), 1 measles, 1
adenovirus, 6 HLA class I and II, 3 T-helper lym-
phocytes, 1 T-suppressor, 5 monocyte/macrophage, 1
natural killer cell (NK cell), 4 blood clotting factors,
and 1 platelet. Specifically, the following antibodies
were tested using the DAD technique: Mycoplasma
fermentans, strain incognitus MAB and rabbit PAB,
courtesy Dr. Shyh-Ching Lo, Armed Forces Insti-
tute of Pathology, Washington, DC; M. fermentans
strain K7 (rabbit) and strain PG 18 (mule), M. pneu-
moniae strain FH (mule), M. genetalium strain G37
(rabbit), M. pirum strain 70-159 (rabbit), M. homi-
nis strain PG21 (mule) and strain MY13330 (rab-
bit), M. orale strain CHI9299 (mule), M. salivarum
strain PG20 (mule), all courtesy of Dr. Joseph G. Tul-
ly, NAIAD, Bethesda, MD; MAB to human T-helper
cell (AXL839M), MAB to CD13 monocyte antigen
(YN-3D8), MAB to Factor VIII (AXL 738M), PAB to
Factor IX (AXL423), polyclonal antibody to Factor
V (AXL422), MAB to von Willebrand factor (Factor
VIII-related antigen) (AXL739M), MAB to platelet
glycoprotein 1b (AXL842M), MAB to T4 helper-
inducer cells (AXL839M), MAB to T suppressor-
cytotoxic cells (AXL830M), MAB to macrophage anti-
gen (AXL841M), MAB to CD13 (monocyte mark-
er) (YNW-3D8-B), MAB to HLA-DR (AXL827M),
PAB to CMV (BX-PU083-UP), PAB to HBV sur-
face antigen (AXL-683), PAB to HBV core anti-
gen (AXL709), PAB to HSV I and 2 (086P),
PAB to HSV I (Macintyre, VR3) (AXL237), PAB
to HSV 2 (MS) (AXL239), PAB to M. bovis
(AXL247), M. duvallii (AXL248), and M. paratu-
berculosis (AXL435), and PAB to E. coli (AXL480),
all from Accurate Chemical and Scientific Corpora-
tion, Westbury, N.Y.; MAB to human CD4 gp55kD
(P42115M), MAB to human monocyte-macrophage
CDllc (P90105E), MAB to human follicular den-
dritic cells (P90106C), MAB to human HLA DQw1
(P6141OM), MAB to HLA class II (DQ) (P42416M),
MAB to HLA-DRw52 (P6151OM), MAB to human
HLA class II DP + DQ + DR (P90103E), MAB to HIV
gp1601120 (C42869M), MAB to HIV 1 (C4531OM),
goat anti-HIV-1 (B65870G), goat anti-HIV-l, IgG
(B65875G), sheep HIV-1 gp120-1 (B1289S), MAB
to CMV 65 kD major matrix protein (C65083M),
chicken anti-CMV AD169 (B85275C), goat anti-
CMV (B65270G), rabbit anti-CMV (B47821R),
rabbit anti-Streptococcus type A (B66885R), rab-
bit anti-Streptococcus type B (B66880R), rabbit
anti-Mycoplasma hyorhinus (B80nOR), rabbit anti-
Candida albicans IgG (B17401R), MAB to Epstein-
Barr virus (C65221M), MAB to HBV surface anti-
gen S protein (C42863M), all from Biodesign Inter-
national, Kennebunkport, Maine; MAB to human
natural killer cells (NK cells) (MABI221), MAB
to HLA common marker (MABI275), MAB to
HIV gp120 IgG2a (MAB883), MAB to HIV gp41
(MAB882), MAB to CMV late antigen (MAB8125),
MAB to CMV IgGl,k (MAB81O), MAB to M. bovis
(MAB970), MAB to M. pneumoniae (MAB828),
MAB to M. avium (MAB968), MAB to Candida albi-
cans (MAB806), MAB to EBV viral capsid antigen
(MAB817), MAB to EBV membrane antigen IgGlk
(MAB813),MAB to adenovirus (MAB8051),MAB to
measles blend (MAB8920), MAB to Varicella zoster
IgG2b (MAB8612), MAB to Varicella zoster IgGl
(MAB8614), MAB to EBV early antigen (MAB818),
MAB to human HIV Nef (MAB899), MAB to Staphy-
lococcus aureus (MAB930), all from Chemicon, Inter-
national, Inc., Temecula, California.
Antibodies and sera were used at the concentrations
supplied (usually ca. I mg of protein per ml). Diffu-
sions were carried out using standard 5% agarose gels
made with deionized water with Tris buffer. Precipi-
tations were read without staining the gels. DAD was
performed on all possible combinations of the sperm
sera with the 75 other antibodies, and all combina-
tions were run at least twice and in the case of posi-
tive results, three times. Over 1800 of the some 2500
possible combinations of the other 75 antibodies have
also been run at least in duplicate, limited only by
the amount of antibody available within our budgetary
constraints.
Results
Protein similarity studies
The results of our search are summarized in Tables
1 through 4. Table 1 displays the homologies found
 215

Table J. Similarities between human CD4 protein and sperm nuclear proteins.

1. CD49-28 HLLLVLQLALLPAATQGKKV
IIII III IIII II I
H2B 98/99-117-118 RLLLPGELAKHAVSEGTKAV
Human histone H2B and H2B.l
2. CD420-36 PAATQGKKVVLGKKGDT
II I I I I II IIII I
HMG-1743-59 APAKKGEKVPKGKKGKA
Human HMG-17 non-histone chromosomal protein
3. CD4156-181 RSPRGKNIQGGKTLSVSQLELQDSGT
IIIIIII I I I III 11111
HMG-1455-80 RGAKGKQAEVANQETKEDLPAENGET
Human HMG-14 non-histone chromosomal protein
4. CD4203-223 AFQKASSIVYKKEGEQVEFS
II I I IIII I
H2BI13-22 GSKKAVTKAQKKDGKKRKRS
Human histone H2Bl (these sequences are nearly identical in all H2B histones)
5. CD4230-250 EKLTGSGELWWQAERASSSKS
III I I I II I I I ! II I
HMG-17310-330 EKLPQEAMVWWKEEAERSSSS
Human HMG-17 non-histone chromosomal protein
6. CD4265-277 RVTQDPKLQMGKK
! II I I I III
H2Bl 15-28 KKAVTKAQKKD.GKK
Human histone H2B 1 (these sequences are nearly identical in all H2B histones
7. CD4279-305 PLHLTLPQALPQYAGSGNLTLALEAKT
1111 II II I II I II ! I
H2B197-122 AVRLLLPGELAKHAVSEG.TKAVTKYT
Human histone H2BI (these sequences are nearly identical in all H2B histones)
8. CD4421-443 RCRHRRRQAERMSQIKRLLSEKK
! 1111111 ! I I II IIII
PROTAMINE 79-100 RSCRHRRRHRRGCRTRKR .. TCRR
Human sperm histone p2 precursor (protamine p2)
9. CD4421-437 RCRHRRRQAERMSQ. IKR
11111111 II I I
PROTAMINE 21-37 RSRRRRRRSCQTRRRAMR
Human sperm histone pI protein (protamine pI)
10. CD4421-447 RC. RHRRRQAERMSQ .. IKRLLSEKKLLSE
11111111 I II I III
H2BI24-51 KDGKKRKRS .. RKESYSIYVYKVLKQVHPD
Human histone H2Bl (these sequences are nearly identical in all H2B histones)

between CD4 protein, protamine, high mobility group
(HMG) chromosomal protein 17, and histone H2B l.
Protamine PI is a histone-type protein found only in
sperm (Meistrich, 1989). As noted above, 70% of
male homosexual and 40% of female AIDS patients
in one study had antibody against protamine (Naz et
at., 1990). HMG-17 is a DNA-associated structural
protein. Its role has not been established (Bustin et at.,
1989) and no information appears to exist regarding
its possible role in AIDS. Histone H2B is found in
many tissues including thymus (which is the essential
organ for T-cell activation), and is unusual in also being
found in sperm. Although in general most histones are
eliminated from the nucleus during sperm formation,
216
tJtere are two major exceptions, and those are histones
HIt and H2Bt (Tanphaichitr et aI., 1978; Wattanaseree
& Svasti, 1983). Unfortunately, the specific sequence
of H2Bt was not available for homology searching, but
all of the H2B family of histones maintain highly con-
served sequences so that little, if any error, has been
introduced (Gabrielli, 1989, Fig. 1).
The observation that histone H2B has significant
homologies with CD4 is very interesting in light of
a discovery by Stricker et al. (1987a, 1987b) of an
autoantibody in the majority of AIDS patients that not
only recognizes an unidentified antigen on CD4+ cells,
but also strongly cross-reacts with histone H2B. Mor-
row et at. (1989; 1991) report that these anti-histone
antibodies correlate with disease activity and loss of
CD4+ cells in longitudinal studies of AIDS patients.
It is also noteworthy that herpes simplex virus
(O'Hare & Goding, 1988; Latchman et at., 1989;
Rhys et at., 1989), cytomegalovirus (Munch et aI.,
1988), and adenoviruses (O'Neill & Kelly, 1988) all
require H2B histone-associated binding sites on DNA
for activation and have been found to trans-activate an
octomeric histone H2B promoter, leading to the obser-
vation that ubiquitinated histone H2B is preferentially
expressed and located on transcriptionally active chro-
matin (Nickel, Allis & Davie, 1989). This functional
overlap suggests that antibody to H2B may result not
only from exposure to sperm, but also either directly
or indirectly from virus infection.
A further homology search using H2B as the search
string yielded two other possible cross-reactive targets
on blood cells for antibody to H2B: CD7 protein, and
beta platelet growth factor receptor precursor protein
(Table 2). Notably, CD7 protein is an early T-cell spe-
cific membrane antigen that is associated with pro-
duction of immature cells in leukemia (Haynes et at.,
1980; Lo Coco et aI., 1989; Thiel et at., 1989). In
the context of AIDS, autoantibody against CD7 might
result in failure ofT-cells to mature, causing significant
loss of not only CD4 cells but of other T-cell subsets
as well. Autoantibody against platelet growth factor
receptor (Table 2) might contribute to the thrombo-
cytopenia that is very common among AIDS patients
(Morrow etal., 1991).
In addition to chromosomal proteins, sperm con-
tains a very high content of mitochondria. These mito-
chondrial proteins would present another set of possi-
ble antigens during antigenic presentation of semen. It
is not surprising to find, therefore, that both mitochon-
drial membrane proteins and several enzymes involved
in the various energy pathways contained in the mito-
chondria have significant homologies with CD4 pro-
tein (Table 3). Particularly noteworthy are the sim-
ilarities between CD4 and creatine kinase, which is
an enzyme required not only for mitochondrial activ-
ity, but for muscle contraction as well. Thus, anti-
CD4 antibody, whatever its source, may cross-react
with both mitochondrial and muscle creatine kinase to
produce weakness and muscle wasting - two promi-
nent symptoms of ARC and AIDS. In the event, these
sequence similarities strongly argue that mitochondri-
al proteins could potentially activate an autoimmune
response cross-reactive with CD4+ cells, and may
account, at least in part, for the frequency of antibody
observed to 'sperm extract' (Naz et at., 1990).
It is important to note that non-protein components
of sperm have also been associated directly with the
induction of LCTAs and could not be found using our
search techniques. Human DNA, such as might be
encountered following repeated exposure to allogene-
ic sperm, can induce LCTAs (Shoenfeld et at., 1985)
and anti-DNA antibodies are very common in AIDS
and lupus patients (Morrow et at., 1991). Oddly, the
resulting anti-DNA antibodies cross-react specifical-
ly with lymphocyte membranes rather than with the
nucleus (Shoenfeld et aI., 1988). Equally oddly, DNA
has been found on the cell surfaces of only two kinds
of human cells: lymphocytes and cancer cells (Lerner,
Meinke & Goldstein, 1971; Aggarwal et at., 1975). In
consequence, lymphocyte-associated membrane DNA
may provide a target for anti-DNA antibodies, so that
they may also act as lymphocytotoxic antibodies in
diseases such as AIDS and lUpus.
When interpreting the data presented in Tables 1-
3, it is also important to bear in mind that sperm is
only one component of semen. Semen also contains
a large number of lymphocytes. Kion and Hoffman
(1991) and Stott et at. (1991) have both demonstrated
in animal models of AIDS that lymphocytes can induce
anti-MHC antibodies that cross-react with HIV. More
importantly, whole blood transfusions and granulocyte
transfusions have led to direct induction of LCTAs
directed at both B cells and T cells in a large pro-
portion of human transfusion patients (Arnold, Gold-
mann & Pfleiger, 1980; Fehrman, Ringden & Moeller,
1983). This result argues strongly for the likelihood
that semen-associated lymphocytes can also produce
LCTAs if immunologically processed. There should
be no need to have to argue that such allogeneic lym-
phocytes have significant homologies with host lym-
phocytes.
 217

Table 2. Similarities between sperm histone H2B 1 and Lymphocyte proteins other than
CD4.

1. H2B196-117 AVR.LLLPGELA.KHAVSEGTKA
I I 1111 II III II I
CD74-27 PPRLLLLPLLLALARGLPGALAA
Human CD7 antigen precursor (gp40) (T-cell leukemia antigen)
2. CD43-24 RGVPFRHLLLVLQLALLPAATQ
III I II I I I I I II I III
CD7315-336 RGVATQRLCVCLRPPPLPTATQ
Human CD7 antigen precursor (gp40) (T-cell leukemia antigen)
3. H2BI93-118 IQTA.VRLLLPGELAKHAVSEGTKAVT
IIII IIII II II I I I II
PGDR 311-335 VESGYVRLL .. GEVGTLQFAELHRSRT
Beta platelet-derived growth factor receptor precursor

Table 3. Similarities between CD4 protein and mitochondrial proteins.

1. CD4100-123 LKIEDSDTYICEVEDQKEEVQLLV
II II I II III I I I I II I I
PDH 1878-1898 LKIEKLKXYICTEETIK.VFXLGL
Hyman pyruvate dehydrogenase beta subunit gene, complete cds
2. CD4 204-226 AFQKASSIVYKKEGEQVEFSFPL
II I I III II IIII I I I IIII
ATPase 867-889 AFPRWTRVPYKRKEAXLRLSFPL
Human ATP synthase beta subunit gene, exos 1-7
3. CD4265-280 RVTQDPKLQMGKKLPL
III I I III I I
MMP173-87 KVTKDG.VTVAKSIDL
Mitochondrial matrix protein p I precursor
4. CD4 269-286 DPKLQMGKKLPLHLTLPQ
I II II I III II I III
KCRS 398-415 EKKLERGQDIKVPPPLPQ
Human creatine kinase, sarcomeric mitochondrial precursor
5. CD4307-354 KLHQEVNLVVMRATQLQKNLTCEVWGPTSPK .. LMLSLKLENKEAKVSR
I I II I I II I I I III I I I I I II I I I III II
KCR 295-356 RLIQERGWEFMWNERLGYILTCPSNLGTGLRACVHIKLPLLSKDSRFPK
Human creatine kinase, mitochondrial precursor
6. CD4438-448 LLSEKKTC .. QCP
IIIIII I I
MMPI 245-255 LLSEKKISSIQ
Mitochondrial matrix protein pI precursor

To summarize, a wide range of semen compo- sperm antigens and CD4 or CD7 proteins (and possible
nents, including sperm surface and nuclear proteins, cross-reactivity with other human proteins) may help
mitochondrial proteins, seminal fluid, lymphocytes to account for subsequent immune suppression.
and nuclear DNA, may all contribute to autoimmu-
nity directed at T-lymphocytes. The protein similari-
ty searches confirm that similarities between relevant
218
Immunodiffusion (DAD) studies
The results of the DAD experiments also confirm the
plausibility of the MAMA hypothesis as applied to
the induction of lymphocytotoxic autoimmunity asso-
ciated with AIDS and ICL. Several of the interactions
predicted by the similarity search were observed.
Although over 1800 combinations of antibodies
were tested in duplicate or higher repetitions, only
results relevant to the question of semen-associated
autoimmunity are being reported in this paper, and
comprise a subset of 150 tests with sperm antibodies
and 294 between Mycoplasma and lymphocyte anti-
bodies, which turned out to be particularly relevant
to the current study. Complete results of the remain-
ing combinations are being reported elsewhere (Root-
Bernstein, 1994). Suffice it to say that only 75 repeat-
able positive interactions have occurred among the
1800 non-sperm-antibody combinations tested. While
this means a 4% positive rate, this rate is misleadingly
high, since the antibodies chosen for testing are not
random, but rather were used because of their prob-
ability of interacting. Furthermore, a positive inter-
action between, say, one CMV and one Mycoplasma
antibody pair was almost always accompanied by fur-
ther CMV-Mycoplasma antibody pairs (8 CMV and
15 Mycoplasma antibodies were tested). Thus, each
positive result was actually accompanied by several
additional confirmational results, artifactually boost-
ing the apparent positive rate. We therefore argue that
our data demonstrate clearly that the positive results
are due to specific interactions.
Further evidence for specificity is provided by evi-
dence against general precipitation of antibodies raised
in particular host species, as might be expected if the
binding sites were on the structural rather than the
hypervariable (or antigen-binding) region of the anti-
bodies. No patterns of positive results were observed
by host species in which the antibodies were raised.
Although several of the observed interactions (e.g.,
precipitation of Candida, E. coli, and BCG and M. avi-
um antibodies by Streptococcus type A - but not type
B - antibody) have no obvious implications for AIDS
specifically, the majority of the 75 positive results
involved immunological interactions between specif-
ic pairs of infectious agents associated with AIDS
and between these antibodies and antibodies against
lymphocyte antigens (HIV + Mycoplasmas; CMV +
Mycoplasmas; HIV + Staphylococcus; and HBV +
Mycobacteria, all of which also precipitated at least
one lymphocyte antibody as well). These results sug-
gest that sperm-associated antigens are not the only
probable causes of autoimmune phenomena in AIDS
- a crucial point that must be borne in mind in inter-
preting the data that follow.
All but one of the 22 positive results of the 454
DAD experiments relevant to sperm antigens and
Mycoplasma antigens which were observed are shown
in Figs. 3-9. All combinations not mentioned in the
following paragraphs (that is a total of 139 anti-
body combinations with sperm antibodies and 283
with Mycoplasma and Mycobacteria antibodies) were
repeatedly negative (no precipitation was visible).
Sperm immune serum raised in sheep against
human sperm (Chemicon) precipitated antibodies
against blood coagulation factors V, IX, and von Willi-
brand's factor; platelet glycoprotein beta (see Table
2); natural killer cells and follicular dendritic cells;
and Mycoplasma fermentans (both Tully - not shown
- and Lo strains) (Figs. 3 & 4). Sperm immune
serum (Arnel) had more limited, but similar, speci-
ficities, precipitating antibodies against blood coagu-
lation factor V (Fig. 5) Mycobacterium avium (Fig. 6),
and Mycoplasma fermentans (Tully) and Mycoplas-
ma pirum (Tully) (Fig. 7). These results strongly sug-
gest that autoimmunity against blood coagulation fac-
tor V may result from immunological exposure to an
appropriate sperm-cofactor combination, and that both
Mycoplasma and Mycobacteria coinfections may play
the role of cofactors for sperm when coprocessed by
the immune system. Extensive evidence has previ-
ously linked Mycoplasmas and Mycobacteria to many
autoimmune processes, including antisperm antibody-
mediated forms (Soffer et al., 1990; Shoenfeld & Isen-
berg, 1988). Furthermore, the coprecipitation of sperm
and Mycoplasma antibodies confirms the chemical
complementarity suggested by earlier research show-
ingthatMycoplasmas can bind to sperm (Black, 1983).
A similar mechanism may be involved in the transmis-
sion of M. avium.
We also found that Mycoplasma fermentans anti-
bodies will precipitate a wide range of anti-HLA class
II protein and macrophage antibodies (Figs. 8 & 9).
These findings, combined with the precipitation of
natural killer cell and follicular dendritic cell antibod-
ies by sperm antibodies, confirm our theoretical pre-
dictions that a combination of sperm and Mycoplas-
ma can induce idiotypelanti-idiotype antibodies that
cross-react with determinants on cells of both CD4
and class II MHC lineages (see Fig. 2). Antibody to
Mycobacterium avium did not precipitate any human
lymphocyte antibody tested (a total of 14) and therefore
 219

Fig. 3. Double antibody diffusion (DAD) study of sperm polyclonalAb (Chemicon) with various human blood protein antibodies. Precipitations
occurred between the sperm Ab(well 0) and antibodies against factor IX (well I), factor V (well 3), follicular dendritic cells (well 4), and
platelet glycoprotein I beta (well II). Unstained. These precipitates model the immune complexes predicted in Figures I and 2.

Fig. 4. DAD study of sperm polyclonal Ab (Chemicon) with antibodies to various blood proteins and infectious agents associated with AIDS.
Precipitations occurred between the sperm Ab (well 0) and antibodies against von Willibrand 's factor (well 4), natural killer cells (well 6) and
Mycoplasma ferm entans, strain incognitus (polyclonal; well 9). An additional precipitation occurred between Ab to Mycoplasma hyorhinus
(well 12) and Ab to HLA DR (well 3). Mycoplasma-HLA complementarity is common - see Figs. 8 and 9. Unstained. These precipitates model
the immune complexes predicted in Figs. 1 and 2.
220

. ,
.. ' t1 '. (2" t7' ~8 ~

,. _). ,,~ " ~.2' 0 .'

~9 ~\
I'~') I-~,~ " (11 ~ b ' ~
,.

Fig. 5. DAD study of sperm polyclonal Ab (Arnel) with various antibodies to blood proteins and viruses. The only observed precipitation
occurred between sperm Ab (well 0) and Ab to Factor V (well 4). Unstained. These precipitates model the immune complexes predicted in
Figs. I and 2.

Fig. 6. DAD study of sperm polyclonal Ab (Arnel) with various antibodies to infectious agents associated with AIDS. The only observed
precipitation was between sperm Ab (weB 0) and antibody to Mycobacterium avium (well 12). Other Mycobacteria did not precipitate sperm
Ab (data not shown). Very weak precipitations also occurred between M. llvium Ab (well 12) and S. aureus Ab (well 7) and Streptococcus type
A Ab (well II) - see text for discussion. Unstained. These precipitates model the immune complexes predicted in Figs. land 2.

appears to have different specificities than Mycoplas- ed rather than a true failure of sperm and HIV anti-
ma antibodies. We also found no HIV antibody that bodies to cross-react (as would be predicted by exper-
precipitated either sperm antibody tested, although this iments reported by other investigators in the Introduc-
negative result may be due to choice of antibodies test- tion, above).
 221

Fig. 7. DAD study of polyc1onal Ab to sperm (Amel) with antibodies to Mycoplasma and Mycobacteria. Precipitations occurred only between
sperm antibody (well 0) and antibody to M. pirum (well I) and M. fermentans (well 4). M. hominus antibody (well 2) and M. pneumoniae
antibody (well 7) also precipitated each other, an observation without obviousrelevance.to the theory being tested. Unstained. Tlfese precipitates
model the immune complexes predicted in Figs. I and 2.

Fig. 8. DAD study of polyc1onal Ab to M. fermentans strain incognitus (Lo) with antibodies to human blood proteins and infectious agents
associated with AIDS. Precipitations occurred betweenM.fermentans Ab (well 0) and HLA DR common MAb (well 3), macrophage polyclonal
Ab (well 5) and HBV surface protein polyc1onal Ab (well 10). Unstained. These precipitates model the immune complexes predicted in Figs. 1
and 2. .
222

Fig. 9. DAD study of M. fermentans polyc1onal Ab (rabbit; Tully) with blood protein antibodies. Precipitations occurred between Ab to M.
fermentans and HLA-2 polyc1onal Ab (well 5), HLA DQw I MAb (well 8). HLA DQw52 MAb (well 9) and platelet glycoprotein 1 beta MAb
(well 11). Unstained. These precipitates model the immune complexes predicted in Figs. I and 2.

The strong co-precipitation of sperm, platelet, and
factor V antibodies is particularly noteworthy, since
a relatively common symptom of AIDS is a blood
coagulation problem that is not treatable by factors
VIII or IX (Morrow et al., 1991). Our data suggest
that treatment with factor V might be beneficial. Also
noteworthy is the possibility that the blood coagulation
disorder is not due to HIV, but rather to sperm-induced
autoimmunity, since inoculation of semen into animals
is also associated with blood coagulation disorders and
cellular fragility (FaviIli, 1931; Metalnikoff, 1900).
Also of possible interest is the precipitation of M.
Jermentans antibody of antibody to HBV surface pro-
tein (Fig. 9). This observation suggests that HBV
and Mycoplasmas may act synergistically in people
who are co-infected, and have the potential to trigger
autoimmune processes.
We must emphasize that these experiments are not
a definitive examination ofthe possible cross-reactions
that sperm and sperm-associated antibodies may have.
The number of cellular and pathogen-related antibod-
ies tested was limited by funds and availability. Thus,
these experiments should be interpreted in terms of
the hypothesis being tested, from which point of view
they were successful. On the other hand, further testing
may reveal that HIV or other infectious agents associ-
ated with AIDS may be able to act as cofactors with
sperm to induce either anti-lymphocyte autoimmunity
or other forms of autoimmunity associated with AIDS.
We must also emphasize that these experiments are,
as far as we know, the first to demonstrate that indepen-
dent antigens can result in pairs of idiotypic antibod-
ies that act like idiotype/anti-idiotype pairs. All previ-
ous experiments describing idiotype/anti-idiotype anti-
body pairs have raised the anti-idiotype antibody from
the idiotype.
Discussion
Autoimmune risks associated with receptive anal inter-
course
The experimental data presented here, in conjunction
with the extensive literature review documenting the
presence of antibody responses to semen antigens and
LCTAs in AIDS, strongly suggest that semen antigens
may playa pathogenic role in AIDS, when processed
by the immune system in the presence of appropriate
infectious or allogeneic cofactors. Sperm has previous-
ly been shown to have CD4-like proteins on its cell sur-

face, and our similarity searching has revealed a wide
range of possible sequences that may represent these
CD4-like regions. Verification that anyone of these
sequences is, in fact, CD4-like in its antigenic potential
clearly will require further experimentation. We have
additionally demonstrated that some of the infectious
agents associated with AIDS induce antibodies that
are chemically complementary to those raised against
sperm, and that some of these antibodies also precip-
itate antibodies against MHC class II proteins. These
data suggest that some of the combination of agents,
such as HIV plus semen, or HIV plus Mycoplasmas,
that are predicted by the similarity searching to be
chemically complementary pairs, are in fact so, and
the data demonstrate that these pairs are cross-reactive
with lymphocyte antigens. Thus, one unique prediction
of the MAMA theory of autoimmunity is satisfied and
its plausibility as a mechanism for inducing autoimmu-
nity bolstered. We caution that the theory is far from
proven. (Such proof will require inducing autoimmu-
nity in animals using appropriate antigen pairs.) We
also caution that these data do not address the ques-
tion of whether alloantigen-induced autoimmunity is
a primary cause of immune suppression in AIDS, a
cofactor, or a symptom. The data simply show that our
understanding of some of the mechanisms underlying
the autoimmunity are a bit more comprehensible than
before, and provide a specific basis for testing ani-
mal models based upon the specific pairs of antigens
described here. If such animal models can be devel-
oped for these and other antigen pairs described in
our other papers, then it will be possible to determine
the extent to which they play primary or secondary
pathogenic roles in AIDS. It will also be possible to
begin developing prophylactic and treatment regimens
appropriate to each autoimmune condition.
An important point needs to be stressed in interpret-
ing both the protein similarity and antibody binding
data just presented. The results of such autoimmunity
may not be limited to HIV-infected individuals. Het-
erosexual women, and homosexual and bisexual men
who engage in unprotected receptive anal intercourse,
may have immunological contact with semen in the
absence of an HIV infection. Such exposure, concomi-
tant with an appropriate antigenic co-factor such as a
simultaneous Mycoplasma infection, would be expect-
ed to induce anti-sperm antibodies that could act as
lymphocytotoxic autoantibodies (LCTAs). One would
therefore expect to find such autoantibodies accompa-
nied by immunosuppression in many homosexual men
(many because of the high rates of STDs in gay men)
223
and some women (some, because of the relatively low
rate of STDs compared with gay men) who practice
receptive anal intercourse, even in the absence ofHIV
infection. This is, in fact, the case.
Kiprov and Anderson (1985) found LCTAs in both
HIV-positive and HIV-negative homosexuals. Pruzan-
ski, Jacobs and Laing (1983) found that all of their
homosexual patients with AIDS or ARC had LCTAs
against both T and B cells, but so did 13 of 17 symptom-
free homosexual men. It is unlikely that all 13 were
HIV-infected during 1982, when this study was con-
ducted. Kloster, Tomar, and Spira (1984) reported sim-
ilar results. Nine of ten AIDS patients had LCTAs,
ten healthy heterosexuals did not, while three of five
healthy homosexual men also had evidence of LCTAs.
Further tests were done on two of these three men,
and both showed significantly depressed T-cell activi-
ty and counts. Cleghorn et al. (1988) also report that
T-cell counts and relative ratios were depressed to an
equal degree in healthy homosexual men in Trinidad
regardless of HIV status. Unfortunately, they did not
test for the presence of LCTAs. Neither did Mur-
ray et al. (1988), but they too found that T-helper
cell counts and activity were nearly identical when
asymptomatic HIV-negative homosexuals were com-
pared with asymptomatic HIV-positive homosexuals,
but both groups were immunosuppressed compared
with controls. In short, these data all suggest that
HIV is neither necessary nor sufficient to cause T-cell
depletion and immunological disfunction in homosex-
ual men, and that other causes of such abnormalities,
such as LCTAs induced by immunologic exposure to
allogeneic cells, may be essential to the acquisition of
HIV infection and for the subsequent transition from
HIV-positivity to AIDS by creating prior immune sup-
pression.
It is important to emphasize that the risk of devel-
oping anti-sperm induced antibodies that also act as
LCTAs is not limited to homosexual men. Many het-
erosexual couples engage in anal intercourse. The anus
is unlike the vagina in several significant ways: it does
not have a thick layer of epithelial cells or mucus pro-
ducing cells to protect it; it lacks the musculature of
the vagina; and the vasculature is much closer to the
surface. The lower intestine is also studded with Pey-
er's patches, which serve as immunological portals for
sampling the intestinal contents. All of these factors
make immunological contact with semen components
much more likely in anal than in vaginal sex. Thus,
it is significant to note that a Kinsey Institute study
(Anonymous, 1988) recently revealed that between 30
224
and 40% of all American women over the past four
decades have experimented with anal intercourse at
some time during their lives, and that as many as 25%
of sexually active women at one midwestern universi-
ty had engaged in anal intercourse at least once during
their college years. These figures are similar to those
reported for university students in Canada (MacDon-
ald et al., 1990). During 1988,5514 first year college
students were surveyed. Of the 69% of the women
who were sexually active, 19% had participated in
anal intercourse at least once, and 5.5% reported a pre-
vious sexually transmitted disease. Among the 8.6%
of the women who had had ten or more partners, how-
ever, 35% had engaged in anal intercourse, and 24%
had had one or more STDs. These data are relevant
to understanding risk for immune suppression, since
several studies have demonstrated that both hetero-
sexual anal intercourse and STD history confer the
same increased risk of AIDS in women as has been
found among homosexual men. We stress again, how-
ever, that simply engaging in unprotected receptive
anal intercourse does not necessarily lead to antigenic
exposure to semen, nor to exposure to the specific com-
binations of antigens that we believe to be necessary to
induce LCTAs. The risk is also a function of what infec-
tious agents are present in the semen, or in the anus, at
the time of exposure, as well as the number of partners
(since the greater the number of partners, the greater
the range of alloantigen challenge and the greater the
probability of an appropriate antigenic cofactor being
present at the time of exposure).
Unprotected receptive anal intercourse has also
been reported to be a significant AIDS risk for spouses
of hemophiliacs (Melbye et al., 1985). The European
Study Group (1989) reports that a study of 153 HIV-
seropositive men and their wives resulted in the identi-
fication of three factors that predisposed to acquisition
of HIV infection: a history of one or more sexually
transmitted diseases in the woman during the past five
years; full-blown AIDS in the male partner; and anal
intercourse (note the combination of STD with anal
intercourse, which is required by the MAMA theory).
Seropositivity among women with none of these risk
factors was 7%, whereas it was 67% among wom-
en having two or more risk factors. Padian, Shiboski
and Jewell (1990) have reported similarly that the two
highest risk factors for heterosexual transmission of
AIDS are repeated anal intercourse and the occurrence
of bleeding during intercourse. These results seem to
be confirmed by a study of 1115 women who attended
a genitourinary medicine clinic in west London dur-
ing 1987. Three of the women were HIV seropositive.
Two of these women completed a questionnaire con-
cerning their sexual history. Both women were in the
upper fifth percentile for lifetime sexual partners, and
both were unusual in having engaged repeatedly in anal
intercourse (Evans et al., 1988). Moreover, all of the
women infected by a male hemophiliac in Great Britain
were found to have engaged in repeated, unprotected
anal intercourse with him (Maddox, 1992; Hodgkin-
son, 1992) and anal intercourse has been reported to
be a risk in many other hemophiliac-associated AIDS
cases (Melbye et ai., 1985). Unfortunately, immune
competence has not been measured in any of these
studies, nor has any attempt been made to determine
if anti-sperm antibodies, Iymphocytotoxic antibodies,
or circulating immune complexes are also associated
with anal intercourse as might be expected according to
the data reported above. It would seem worthwhile to
carry out such studies since the degree to which semen-
associated autoimmunity may predispose or contribute
to AIDS is clearly of importance.
Acquired immunosuppression unassociated with
HIV can be sufficient to lead to opportunistic infection.
Cases of opportunistic infections including Mycobac-
terium avium intracellulare, esophageal candidiasis
and Kaposi's sarcoma have been reported repeated-
ly in HIV-negative homosexual men and drug addicts
(reviewed in Root-Bernstein, 1990a; 1993) and many
hundreds of HIV-free AIDS cases - now subsumed
under the name idiopathic CD4-T-cell Iymphophenia
(lCL) - have now been recorded by the Centers for
Disease Control (Atlanta, GA, USA). For example,
recently Macon et al. (1993) have characterized a
homosexual male patient with Kaposi's sarcoma and
atypical lymphoma without signs of HIV or HTLV-
I or II infection who developed Pneumocystis pneu-
monia and died of disseminated Cryptococcus neofor-
mans infection. His T-cell count at diagnosis was only
43/mm 3 . He was, however, infected with Mycoplas-
mafermentans - a clearly relevant finding in light of
the results reported here (see also Soffer et ai., 1990).
Similarly, Tsatsoulis and Shalet (1991) have character-
ized a 26 year old man with polyglandular autoimmune
(PGA) syndrome, characterized by Addison's disease,
hypoparathyroidism, chronic mucocutaneous candidi-
asis, and alopecia totalis (all of which are symptoms
of T-cell suppression and are also common features
of AIDS). He also had extremely high levels of sperm
antibody, which could have been a very likely cause, or
at least a significant mediator, of his clinically-apparent
immune suppression.

It is important to stress that the results obtained in
our experiments strongly support the work of Mon-
tagnier and Lo concerning a primary pathogenic role
for Mycoplasmas in AIDS etiology (Montagnier et al.,
1990; Lo et al., 1991). At the same time, we stress that
Mycoplasmas are only a part of a larger pathogenic
picture that includes immunologic exposure to semen
components, allogeneic lymphocytes, HIV, CMV and
other infectious agents, and that it is too simplistic to
attribute AIDS pathology to any single agent or mecha-
nism. We therefore interpret our results conservatively
to mean only that sperm-associated autoimmune pro-
cesses can playa role in AIDS, but not that they are a
necessary or sufficient factor for AIDS causation.
Thus, semen-induced autoimmunity directed at
lymphocytes may be a cause of immune suppression
independent of HIV infection (though it is certainly
not the only cause) (Root-Bernstein, 1990a, 1990b,
1990c; 1993); it may predispose individuals to con-
tracting an HIV infection or it may act as a co-factor
or stimulus to HIV replication that contributes to the
development of full-blown AIDS following infection.
At this point in time, existing data do not allow us
to choose between these alternatives. We therefore
suggest that prospective studies of the immunologi-
cal status of individuals who engage in frequent or
promiscuous unprotected anal intercourse both in the
presence and absence of HIV infection would be of
great importance to our understanding of the etiology
and pathogenesis of AIDS, and perhaps lead to greater
understanding of the immune suppression that often
precedes HIV infection in high risk individuals.
Further epidemiologic and experimental tests of the
role of autoimmunity in AIDS and ICL
A number of testable issues need to be addressed con-
cerning the possible roles of lymphocyte and sperm
antigens as inducers of pathologic autoimmune pro-
cesses in AIDS and ICL. First, we are not claiming
that such autoimmunity is the cause of either syn-
drome. Rather, we are making the much more limited
claim that these agents may be inducing clinically rele-
vant pathological events that may range from severely
immune suppressive to merely additive immunological
burdens. Thus, we have two responses to the common
argument that if semen were a 'cause' of AIDS, AIDS
would be as old as mankind, since homosexuality is
undoubtedly as old as mankind. Our first response is
that we are not claiming that exposure to semen is suf-
ficient to cause AIDS. That is something that needs to
225
be elucidated by experiment. More importantly, people
who make the 'homosexuality-is-as-old-as-mankind'
argument ignore two limitations to our 'epidemiologi-
cal' evidence from the past.
First, the diseases that are diagnostic for AIDS in
the absence ofT-cell tests and HIV tests are all extreme-
ly difficult to diagnose, and all of them (save Kaposi's
sarcoma and disseminated tuberculosis) were discov-
ered and became readily diagnosable only in the past
30 to 40 years (Root-Bernstein, 1993). Furthermore,
prior to the antibiotic era, people who developed severe
immune suppression would have been more likely to
die of much more common diseases, such as syphilis,
tuberculosis, or sepsis, than of the rare opportunitistic
infections we see today (Root-Bernstein, 1993). Thus,
prior to the antibiotic era, it would have been extremely
difficult to identify AIDS, even if it existed, although
hundreds of cases meeting the surveillance definition
of AIDS are known back to 1872 (Root-Bernstein,
1990c; 1993).
Also to the point, homosexual behaviors have
changed radically over the centuries. Upper class gay
men in Greece and Rome, for example, were forbidden
to allow themselves to be entered sexually. Anal inter-
course was practiced only on social inferiors (Aries &
Duby, 1987). In other words, socially superior men
2000 years ago would have had very low probabili-
ties of contracting AIDS, whatever the cause or caus-
es of AIDS. Since most of our medical records from
antiquity are by and about socially superior men, and
since these medical men did not have the disease cate-
gories necessary to observe AIDS-like symptoms, they
are unlikely to record AIDS-like symptoms even if
they had been present. In short, historical evidence is
largely irrelevant to the present question.
The present questions are of mechanism and patho-
genesis: What causes lymphocytotoxic autoimmunity
in AIDS, and what role does this autoimmunity play in
AIDS? We want to stress that sperm-induced autoim-
munity, like may other forms of autoimmunity (West-
all & Root-Bernstein, 1986; Root-Bernstein, 1990b,
1991) probably either requires or can be promoted by
infectious co-factors such as HIV, cytomegalovirus, the
various hepatitis viruses, chlamydia, and other sexual-
ly transmissible agents (Root-Bernstein, 1990b; Root-
Bernstein & Hobbs, 1993). Therefore, we are not argu-
ing that immunological exposure to sperm by itself will
necessarily lead to lymphocytotoxic autoimmunity.
There are certainly many reports of AIDS-associated
diseases being transmitted by anal intercourse in the
absence of HIV both in homosexual men (Morson,
226
1964; Felman & Nikitas, 1979; Turner, White & Sout-
ter, 1990; Buimovici-Klein et at., 1990) and in women
(Rabinowitz, Bassan & Robinson, 1988). The impor-
tance of these infectious agents as possible co-factors
in inducing autoimmunity is emphasized by the obser-
vation of numerous homologies between CMV, EBV,
HSV, HBV and other infectious agents and the CD4
protein of T-helper cells (Root-Bernstein & Hobbs,
1993).
Given the large amount of data demonstrating
many similarities between semen-associated compo-
nents and lymphocyte proteins, and the widely vali-
dated role of lymphocytotoxic autoimmune process in
AIDS, it now becomes manifestly important to perform
new types of animal experiments (Root-Bernstein,
1990c, 1992b, 1993). The role of semen-Mycoplasma,
HIV-semen, or HIV-semen-Mycoplasma synergism
could be evaluated by inoculating chimpanzees or
macaques rectally with these combinations and eval-
uating both the production of LCTAs and the rate
of development of immune deficiency as compared
with animals inoculated with single agents. Similar
experiments could be performed to evaluate allogene-
ic lymphocyte-Mycoplasma, allogeneic lymphocyte-
HIV, and allogeneic lymphocyte-HBV (or other virus-
es) effects when inoculated intravenously, as occurs
in drug abuse and transfusion. Finally, many of these
same experiments can be performed on non-primate
models to determine whether actual HIV infection is
necessary for development of LCTAs and immunosup-
pression, or if simple antigenic stimulation (i.e., pro-
duction of antibody) with appropriate pairs oftransmis-
sible agents may be sufficient to trigger autoimmunity.
The importance of experiments to model the induc-
tion of autoimmunity in AIDS and ICL cannot be over-
estimated. No animal infected with HIV has ever dis-
played evidence ofLCTAs or CICs (Clerici et at., 1993;
Zarling et at., 1990; Stricker et at., 1987b). No animal
infected with HIV has ever developed AIDS, either.
On the other hand, development of LCTAs and CICs
in human beings at risk for AIDS and ICL is as high-
ly prognostic of death as any HIV-related measure of
health, whereas absence of LCTAs and CICs is high-
ly predictive of continued health and normal T-cell
counts, even among HIV-infected people (Szabo et at.,
1992; Zarling et at., 1990; Sonnabend, 1989; Ozturk
et at., 1987; Stricker et at., 1987a; 1987b; McDougal
et at., 1985). These observations strongly support the
contention that autoimmune phenomena are central to
AIDS (as opposed to HIV infection), whether their
mechanism(s) of induction turn out to be due to semen
components, allogeneic lymphocyte exposure, multi-
ple concurrent infections, or some combination(s) of
these (Root-Bernstein, 1990c, 1993; Root-Bernstein &
Hobbs, 1993). We are not dogmatic about the possible
causes of autoimmunity in AIDS - only that we must
find its causes, whatever they turn out to be.
Moreover, we firmly believe that there can be no
cure for AIDS without a concomitant cure for the
autoimmune phenomena that plague all people with
AIDS, for it is the nature of autoimmune processes to
progress independently of the agents that initiate them
(Root-Bernstein, 1991, 1993). No greater calamity
could befall AIDS research than to learn how to control
HIV, but still have AIDS patients die of uncontrolled
autoimmune processes, or to have people return to high
risk behaviors, thinking that they are safe because they
cannot get HIV, only to find that there are causes of
autoimmune destruction of the immune system that do
not require HIY.
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© 1996 Kluwer Academic Publishers.
AIDS and good theory-making *
Steven B. Harris
Dept. of Pathology, Center For Health Sciences, University of California at Los Angeles, Los Angeles, CA 90024,
USA
Induction: the problem ofinferring causation
from correlation
Since the writings of the 18th century philosopher
David Hume it has been known that certainty about
physical causes and effects is not to be had from mere
association, even if the temporal sequence is correct.
In fact, according to Hume, absolute certainty about
positive causation is not to be had, even when we can
do direct experiments - but most scientists ignore this
most extremely pessimistic view of causal knowledge
(or else they view the high degree of inductive certainty
gainable with experiment to be 'good enough').
It seems that Hume is at least correct that to some
extent the causal conclusions of science are always
uncertain, because they involve mechanisms and rules
we can never be completely sure of understanding,
even if we had some way to guarantee that future
events will continue to be bound by any 'rules' we can
be sure we understand now. (A favorite fable which
philosophers tell to illustrate the problems of induc-
tion features a turkey on a family farm who observes
that every time the farmer comes to his turkey-run, he
comes to feed the turkey. The turkey thus hypothesizes
a causal connection, and predicts feeding each time
the man comes, and as time goes on, sees this theo-
ry 'verified' many times. But on the third Thursday
of November the turkey's well-verified theory sudden-
ly becomes mal-predictive, because the universe is a
much more complicated place than turkeys can com-
prehend. Humans are sometimes in the same position,
with human science: unfortunately, the universe is such
a complicated place as to sometimes make turkeys of
us all).
• This publication is a relatively small excerpt from a longer
article for the lay public, reviewing the mv/AIDS hypothesis and
its critics, which appeared in: Skeptic Magazine, vol. 3(2), pp. 42-79
(1995),2761 N. Marengo, Altadena, CA 91001.
231
Nevertheless, to the extent that today's future,
which we cannot know, continues to be like yesterday's
future, which we can check, progress can be made.
Meanwhile, we may say that even partial understand-
ing of causes brings partial knowledge. Knowledge is
uncertain the way a weather forecast is uncertain, but
this does not mean that science does not uncover a cer-
tain kind of truth. A weather forecast may not guarantee
the future, but the point is that it is usually better than
the results of flipping a coin or guessing. Probabilistic
knowledge, therefore, is still genuine knowledge of a
special kind. In fact, it is the only kind of knowledge
we can have about the future.
Because the association of events may be always
controlled by a third factor we do not suspect, the
problems with induction become most acute in teasing
out causal relationships in systems where we cannot
influence events. In such systems, statistics help us tell
which factors are important and independent of each
other in predicting future events, but these data only
suggest causation when present, since any good pre-
dictive factor found by association may still only be
merely a good 'proxy' for a more truly predictive, or
mechanistically causal factor. Pure associative statis-
tics are far more helpful in ruling out possible causes
than ruling them in, since it is very difficult for a factor
to be independently causal if it is not at least indepen-
dently predicative.
An example may be helpful: if we find from a mul-
tivariate analysis of (say) food sales and crime, that
weekly ice cream sales during a calendar year predict
juvenile delinquency arrests from week to week, but
spaghetti sales do not, this is reasonably good evidence
on the face of it that spaghetti sales are NOT causally
connected to juvenile delinquency. For ice cream and
juvenile delinquency, the associative connection found
by the statistics is merely suggestive - here we may be
looking at cause and effects - or more likely we may
232
be looking at a variable which is a proxy for something
else which is more directly causal of delinquent behav-
ior. But if we doubt such causation for other reasons,
we must guess what the real causal variable is, before
statistics can help us further.
If we find that, say, the daily average temperature
predicts juvenile behavior even better than ice cream
sales predict it, and that knowledge of ice cream sales
gives no predictive power independent of knowledge
of temperature, then we now have evidence that ice
cream is not causal, but is merely a proxy, or marker,
for temperature during the year. Even with this better
association, we are still not assured of the causal role of
temperature, although we might guess for mechanistic
and even indirect experimental reasons that we are
closer to the right track for temperature than we were
with the ice cream sales. So we've made progress. This
story, though silly, illustrates a major path by which
science in general makes progress.
Good and bad theory-making: Occam's razor and
the multiplication of hypothetical causes
As in the example above, to make progress in sci-
ence requires that we continue to propose new and
better causal factors for effects which interest us, and
then test these putative causal factors statistically and
experimentally. Independent prediction serves as the
best statistical test for factors which we cannot vary
experimentally. The power of prediction is thus all-
important in evaluating candidate causal factors for the
cause of effects which we cannot directly manipulate,
such as AIDS.
As noted, statistics cannot do independent thinking
for us, and we must rely on something other than statis-
tics to come up with our list of possible causal factors
(such as the average temperature in the example) to
test with our statistical methods. This is the business
of the human imagination, and very possibly also the
human sense of order and beauty. It has been observed
by the late Karl Popper, noted philosopher of science,
that almost no theory is ever absolutely ruled out (falsi-
fied) by experiment, because with enough imagination,
nearly any theory can be tinkered with after the fact,
so that it continues to 'explain' all data. If one causal
factor does not explain results statistically in a given
situation, it is not necessary to drop it - one may instead
postulate an additional factor which explains results in
the case where the first one fails. In fact, if one persists
in hypothesizing new factors each time an old factor
fails, one need never drop any old hypotheses at all.
At some point, however, doing this makes any theo-
ry simply too ugly and ungainly to be believed, and
at that point (if a better alternative is in view) many
scientists may decide to discard the old theory (Wein-
berg, 1992). (Or at least most scientists will- for as
Max Planck pointed out, only death removes the last
die-hard believers in some theories).
When it comes to AIDS, it is possible to construct a
theory in which AIDS is not caused by the single infec-
tious agent HIV, but instead a theory with so many other
causal agents that it still covers all the available evi-
dence. To do so, however, requires that AIDS, a newly
emerging simultaneous and significant cause of mor-
tality in many diverse groups of people, be explained
rather 'unnaturally' (at least to this author's sense of
such things) in a great number of different ways. For
example, Duesberg suggests that AIDS in Africa is
caused by malnutrition and tuberculosis and new mis-
classification, in U.S. male homosexuals by a new habit
of recreational nitrite use, in female IV drug abusers
and their newborn children by newly popular drugs
other than nitrite, and in many of those HIV-positive
people who do not use illegal drugs by use of prescrip-
tion AZT, new since 1987 (Duesberg, 1992).
Duesberg also suggests AZT use as a risk factor,
despite no good evidence that AZT use increases AIDS
risk for any HIV positive group (Ragni, Kingsley &
Zhou, 1992; Kopec-Schrader et al., 1993; Hendriks et
at., 1993). Deaths in non- drug-using groups like peo-
ple with hemophilia in the pre-AZT era are explained
as being due to immune suppression and extra life
extension by clotting factor concentrate, new since the
early 1970s (Duesberg, 1992, p. 219; but see Johnson
et at., 1985 for counter-evidence).
For none of these suggested causes of AIDS is there
any mechanistic or experimental evidence of good
quality, since none of the agents proposed, or any-
thing related to them, causes in animals the severe and
specific suppression of CD4+ lymphocyte suppression
numbers characteristic of AIDS. In Duesberg's theory,
AIDS deaths from transfusions are argued to be non-
existent (Duesberg, 1992, p. 214), rejecting the ortho-
dox idea that simple transfusion or trauma-associated
mortality usually covers them up (but see Colebunders
et al., 1991). AIDS deaths in contaminated hospital
workers are rejected as anecdotal and perhaps due to
something else, such as personal drug use (Duesberg,
1992, p. 211). AIDS deaths in wives of men with
hemophilia (and their children) are dismissed as being
due to normal ageing, misclassification, etc.

One of the chief arguments against this kind of theo-
rizing may be aesthetic, but a less subjective matter has
to do with utility. Because there are no statistical data
to estimate a quantitative role for many non-orthodox
postulated risk factors for AIDS (such as immuno-
suppression from undiscovered viruses or from certain
unstudied behaviors) the problem with very complicat-
ed post hoc explanations is that they are 'retrodictive',
but not predictive.
If HIV is only a proxy factor, or marker, for a
number of habits or practices which are supposed to
'explain' immune failure better than HIV infection
does, then it follows that the quantitative and even
the qualitative presence of such problems should be
(in theory, at least) usable to predict future develop-
ments of AIDS in asymptomatic people, to even better
accuracy than HIV status does. Nothing of the kind has
been shown, however. On the contrary, cohorts of HIV-
positive people have been found to develop AIDS at a
predictable rate, fairly independently of most of the fac-
tors that have been suggested by heretics to be the real
causal factors for which HIV is merely a marker. (The
reader may see Hendriks et al., 1993, and internal ref-
erences, and also the review in Rosenberg, Goedert and
Biggar, 1994, for studies of the development of AIDS
over time in prospectively tracked cohorts of HIV-
positive male homosexuals, people with hemophilia,
and transfusion-infected people).
Duesberg's hypothesis, as compared with Root-
Bernstein's, actually has the charm of a certain simplic-
ity, since for Duesberg immune failure is said to be due
to only two categories of toxins: foreign blood proteins
or drugs. In Duesberg's view, these two causal factors
are supposed to have independently (and, apparent-
ly, coincidentally) begun producing an epidemic of
immune deficiency in 1) people with hemophilia and
2) everyone else - both starting in 1982 or so.
'Multifactorial' hypotheses such as Root-Bernstein'S,
however, posit so many different contributing causes of
severe immunosuppression (again, failing to differenti-
ate between significant ones and non-significant ones)
that one or more of the putative additional risk-factors
identified by Root-Bernstein is likely to be present in
addition to HIV, in almost every AIDS case. Rethink-
ing AIDS argues the case that besides HIV infection,
AIDS might be caused by blood product infusion (both
whole blood infusion and clotting factor concentrate
injection), by surgery and/or anaesthetics, by acci-
dental trauma, by age (both extreme youth and old
age), by use of any and all common illicit drugs and
most pharmaceuticals (especially antimicrobials used
233
in AIDS), by concurrent infection with any of dozens
of micro-organisms (known and unknown), by rec-
tal insemination, by malnutrition, and even by sunlight
exposure. Considering all these hypothetical cofactors,
Root-Bernstein writes (Root-Bernstein, 1993): 'If such
agents exist ... it is not enough to demonstrate that HIV
is present and highly correlated with AIDS. It is also
necessary to demonstrate that these other agents are
not present in AIDS patients. That is impossible'.
Here Root-Bernstein far overstates the case, since
the standard use of epidemiologic statistics allows for
methods for testing putative risk-factor contributions
in ways far more subtle than looking for people with
simple presence or total absence of all factors being
assessed! . Far more important to the issue of causation,
for those putative risk-factors which can be quantified,
is what the mathematical effect of a larger 'dose' of
one factor is upon the total risk, independently of the
others. Example: is cancer risk smoothly increased by
smoking more cigarettes per day, other factors being
equal? If so, that tells us something very suggestive.
Are smokers who spend various amounts of time in
the sun, from a little to a lot, at larger risk with each
larger increment of sun exposure, all other factors held
equal? If not, this tells us something too.
In general, it is not necessary statistically to find
cases where each factor which is a possible cause of a
disease is totally absent in order to amass evidence that
the factor in question is not causal. It is merely enough
to show that the increasing or decreasing quantitative
presence of the factor in any 'experiment of nature' has
no independent statistical effect on probability of the
disease. Such a demonstration never rules out causa-
tion completely (due to annoying problems with induc-
tion which always allow for the insertion of additional
hypotheses to 'explain' failures in prediction), but it
does make causation much less likely for those who
like their hypotheses as simple as possible.
Such statistical tools (i.e., multivariate analysis)
are among the most powerful which scientists can use
for exploring initial possibilities for causation in com-
plicated and difficult-to- manipulate systems. Without
such statistical tools, for instance, it would never be
I Refusal to use statistical non-correlation to reject a causal
hypothesis (instead, merely adding another hypothesis), along with
refusal to accept statistical correlation as supporting evidence to
accept a hypothesis, amounts essentially to complete rejection of
epidemiologic statistical methods as falsification tools. Complete
'Hume-ian' skepticism of induction allows for this, but this author
has yet to find an HIY/AIDS skeptic who does not use both posi-
tive and negative statistical correlations to buttress favorite non-HIV
causal hypotheses.
234
possible to exonerate anyone of any common set of
behaviors (such as drinking coffee, walking, or eating
certain foods) from a causative role in ANY disease.
The reason is that we live in a complicated world, and
participation to some extent in one or more of a certain
set of behaviors describes ALL of us, and certainly all
of us who develop diseases. But we are fairly certain
that walking and driving a car (for instance) do not
contribute to (say) lung cancer, because of multivari-
ate analysis of life-style, NOT because somebody has
described a group of lung cancer sufferers who never
left their houses.
The following example may illustrate how, if too
many un-quantified factors are postulated to explain an
effect, statistical science cannot help us sort through
them, since only quantification can separate effects or
lack of effects of possible risk factors which are widely
prevalent.
For our example, consider a new hypothetical 'mul-
tifactor' theory that (say) lung cancer is caused not by
smoking, or at least never entirely by smoking, but also
by 'hidden immunosuppression' generated (say) by:
certain kinds of sexual contact, exposure to unshielded
sunlight, exposure to recreational and pharmaceutical
drugs, chronic stress from depression and urban life,
previous surgeries, and concurrent infections (includ-
ing lung infections by herpes and other chronic virus-
es). If we generate a long enough list of hypothetical
co-factors for lung cancer, we will have found, for
almost everyone who smokes and develops lung can-
cer, some hypothetical 'risk-factor' other than smok-
ing, which has never been measured quantitatively in
relevant groups. If, in addition, the very few people
with cancer who smoke, but deny all of our new hypo-
thetical risk factors, can be dismissed as being of ques-
tionable veracity, we will have constructed a brand new
'multifactorial' hypothesis of lung cancer. This theory
will be complicated, difficult to test, and not possible to
evaluate statistically immediately, because the data do
not exist to do it, nobody having previously bothered
to measure them.
But just what good have we done by constructing
such a new theory? Just how useful would our new
model be? If for none of our new hypothesized risk
factors can the extent of exposure to them be used
now to statistically predict lung cancer risk indepen-
dently of smoking (in the way that, say, fruit intake,
age, or radon exposure can), then none of our newly
hypothesized risk-factors are useful at all. Would we be
justified then in using their possible existence to berate
scientists who would like to focus study on known sta-
tistically independent explanatory risk-factors for lung
cancer, such as smoking, age, diet, and radon-radiation
exposure? Would we be justified, having done noth-
ing more than having constructed a new hypothesis of
lung cancer involving new un-quantified variables, in
writing books on our new causal proposals with chap-
ter subtitles like: 'How could so many scientists be so
wrong?' (Root-Bernstein, 1993, p. 350).
The answer is no. Formless hypotheses involving
large numbers of unknown etiologic factors which will
be prohibitively expensive to search for until we have
some better indication of where it will be most prof-
itable to look do not help the cause of human knowl-
edge. When considering complicated multi-factorial
hypotheses, where most of the multiple factors are
missing or un-named, one is reminded of the great
physicist Wolfgang Pauli being asked if he thought the
theory in a new scientific paper was wrong, and his
remark that that would be too kind. Said Pauli: 'It isn't
even wrong'.
In the case of the AIDS heretics, actually, the sit-
uation is even more extreme than in our lung cancer
example, since in the case of AIDS, statistical data DO
exist to evaluate some of the heretically proposed 'co-
factors' for AIDS. The statistical influence of many
of these (illicit non-injected drug use, AZT use, total
clotting factor concentrate use) have been found to
be statistically not independent of mv exposure, and
their AIDS-risk predictive power disappears complete-
ly in study after study, when mv status is controlled
as a variable. All these proposed co-factors, then, are
proxy variables. There is thus very little justification in
continuing to advance hypotheses which involve them,
since none have passed even the most basic initial sta-
tistical standards used by epidemiologists.
Impact of belief on action
As we have seen, epidemiologic criteria implicate HIV
as the causal agent in all AIDS cases, so long as AIDS
is defined very narrowly (and most usefully) as the
newly epidemic syndrome of life-threatening immune
failure (not mild immune suppression) which occurs in
certain groups of body-fluid exposed people at risk for
an acquired infectious disorder. Moreover, an exam-
ination of the pathogenesis of virally-caused immune
failure and death in animals infected with viruses relat-
ed to mv demonstrates that it is quite possible that
mv operates in humans to cause the same sequence
of biological events as we see in AIDS.

As regards the last, the retrovirus 'proof of mech-
anism' information is useful, if only in a negative
way. As we have seen, because of such information
it does no good for heretics to express disbelief that
there could be any mechanism for retroviruses to do the
immunologic damage which orthodox medicine thinks
they do (perhaps the common theme of every hereti-
cal HIV/AIDS argument). Since we know from direct
experiment that retroviruses do in fact do this kind of
immune damage in animals, even in the presence of
serum immunity and with low blood viral levels, we
know such a mechanism must exist in animals. Thus,
such a mechanism is not unlikely to exist in humans
as well. The fact that we have not found yet what we
logically know must be there in animals should not
bother us too much, and by extension, the same is true
of our lack of success so far in humans.
Let us frankly admit it: we know very little of the
actual molecular mechanisms behind most of the causal
sequences which we have identified by experiment in
biology. Thus, at this point the fact that we don't yet
know exactly how HIV and other retroviruses work is
no more and no less odd than the fact that we don't
yet know exactly how cancer, or fetal development,
or memory, or the ageing process works. Complaining
in 1994 that we've spent a decade and lots of money
on AIDS - or for that matter the ageing process, or
embryo development, or cancer, or the basis of bio-
logical memory - and only gotten more bogged down,
is childish. This list of biological problems includes
some of the most complex problems science will ever
face - so tough, in fact, that in the 20th century we're
undoubtedly simply out of our league as regards most
of them.
When Root-Bernstein assails the idea that HIV
causes AIDS completely by itself, with no input from
the immune system of the host or the circumstances
of infection, he assails a straw man, simply because
all infectious diseases are known to be influenced
by inoculum and host defense, and there is certainly
no reason to believe that HIV infection is an excep-
tion. Intrinsic qualities of the host which are impor-
tant in all diseases, and so too presumably for an
HIV-caused AIDS, would include ordinary variations
in genetically-determined immune response, and also
things like host age. These qualities we may term
'intrinsic' host factors. Root-Bernstein refers to host
age as a 'cofactor', but for our purposes it may be more
useful to differentiate intrinsic host factors, which can-
not be changed, from more conjectural environmental
cofactors, which might be subject to manipulation -
235
such as diet, dangerous habits, or infection by other
organisms which are susceptible to antibiotics.
It is, I believe, generally assumed by orthodoxy
that risk of HIV infection is influenced by such stan-
dard infectious disease variables as virulence of the
HIV strain, amount of the HIV virus inoculated, and
route of inoculation into the body (which will not be
independent of amount inoculated). The role of none of
these things is fully understood for HIV infection, but
the idea that there is a large role to be found for each
of them, when we finally understand AIDS more com-
pletely, is not really controversial. Controversy in the
AIDS field is almost entirely centered about the role of
conjectural extrinsic cofactors which are manipulable
after the time of HIV infection, and thus not related
to sexual mechanics, the genetics or age of the host,
or the inoculum and virulence of the HIV strain in
question.
Again, Root-Bernstein differentiates between
AIDS theories in which HIV 1) plays a necessary role
along with such additional and also necessary con-
jectural extrinsic cofactors; and 2) those theories in
which HIV may playa role in AIDS, but is not neces-
sarily required. The latter theories, in which HIV may
contribute to AIDS but is not required, all suffer (like
Duesberg's hypothesis that HIV is totally harmless)
from the problem that full-blown AIDS, as defined by
very low CD4+ lymphocyte counts seen epidemically
in groups at risk for acquired immune failure, is essen-
tially never seen without HIV being present. Again,
this is true for no other infectious agent. It would be
odd indeed if an infectious agent which is not at all
necessary for AIDS is the only agent always found to
be present. Similarly, the theory that AIDS is caused in
homosexual men by drug use rather than an infectious
organism cannot explain the early-discovered, very
significant statistical association between promiscuous
homosexual behavior of donors and transfusion-AIDS
development in strangers who received blood-products
from them (Curran, Lawrence & Jaffe, 1984).
By contrast, theories which posit that HIV is nec-
essary for AIDS but that other immunosuppressive
extrinsic cofactors are necessary also are more diffi-
cult to evaluate. We have examined a number of the
arguments against specific proposals for hypothetical
necessary extrinsic co-factors - such as licit and illicit
drugs, specific micro-organisms, and blood-product-
effects on the immune system - and noted that studies
do not find them to be borne out by statistical regres-
sion. We have also argued that intrinsic host factors
(e.g. viral strain, viral dose), plus extrinsic cofactors
236
like sexual mechanics factors and the presence of other
mucosal lesions (as from sexually transmitted diseases)
at the time of mv infection, are sufficient to explain
all variations in AIDS epidemiology. Of course, there
is no guarantee that nature will not prove to be more
complicated than our simplest theories. If this extra
complexity proves to describe AIDS, however, we
shall have to wait for clues that it does, in order to
know how best to proceed toward a more complicated
hypothesis. Such clues, as argued above, have not been
forthcoming.
How important is it that we understand causation in
AIDS as fully as we can, and as soon as we can? Obvi-
ously, having a more realistic view of the pathogenesis
of AIDS matters, in that it partly determines where we
put research dollars into prevention and treatment stud-
ies, to say nothing of insurance dollars into standard
clinical practices. If mv is merely a bystander virus,
it won't be very helpful to study it, and it may even
be counterproductive to treat it, if the treatment carried
some risk of its own (as ALf and similar drugs certain-
ly do). Similarly, even if lilv is only partly causal in
AIDS, if another cofactor modifiable after mv infec-
tion is necessary for the development of AIDS as well,
then (as Root-Bernstein points out) AIDS might be
prevented or cured by treating something which we
have some control over, even after a person shows up
mY-positive. This would give us something to do to
improve or even guarantee health in mY-positive peo-
ple, and that something might be more effective than,
and not as dangerous as, taking long term antiviral
medications.
The correct view of the pathogenesis of AIDS
should also be important in prevention as well. If mv
is merely a bystander virus, there would be no more
reason for an mY-positive person to tell a prospective
sexual partner about a previous infection with mv
than there would be to tell about a childhood case of
chickenpox. And there would be no more (and no less)
reason to use a condom if one was mY-positive than if
one was not. Obviously, an incorrect view of the patho-
genesis of AIDS might be dangerous and expensive to
many people with the wrong idea (and their sexual
partners), no matter which view ultimately turns out to
be correct.
Prevention, of course, does not only apply to sexual
transmission: if viral theories of mv causation are
correct, we should shortly see the positive effects on
crude mortality rates, as a result of preventing people
with hemophilia from becoming mY-infected from
their clotting factor concentrate, an intervention begun
in 1985-1986. If this does not happen (and because
of the long latency of this disease it is too early to
tell now), we will know that we missed something
very important. Duesberg has already proposed that
we save the money that the mv test for every pint
of donated blood costs us, and stop doing it. If we
cannot with time prove that halting blood-borne mv
infection has stopped transfusion-associated AIDS, to
say nothing of almost all AIDS in younger people with
hemophilia, we will have little excuse for continuing
to test blood or clotting factor concentrate.
Alternative views of the cause of AIDS are prob-
ably becoming more popular today, simply because
they offer more hope than conventional views of the
cause of this disease. A virus is implacable, especially
one hiding in the DNA so intimately that it is part of
the genetic fiber of one's being. It would be preferable
to some to believe that AIDS is due to a combination
of more tractable problems. This possibility has led to
some unusual biomedical research suggestions: Root-
Bernstein suggests (Root-Bernstein, 1993, p. 369):
'If the multifactorial, synergistic theory of AIDS
is valid, then treating mice, rats or rabbits with
some combination of, say, multiple blood transfu-
sions, cytomegalovirus infection, anaesthetics and
surgery, and opiate painkillers could well result in
the immunological suppression typical of AIDS'.
And maybe not. The idea that a lot of small
immunosuppressions might add up to a large one is
an interesting idea, but thin fare to base anything but
a grant proposal on, until the experiment is actually
done. In this author's opinion, it would certainly be
inexcusable to base a book which advocates changes
in the standard management of an often fatal disease
on such theorizing (Root-Bernstein stops just short of
this, but many of his readers do not).
By contrast to the multifactorial immune suppres-
sion 'hypothesis' (if such a vague entity is worth of the
term) of AIDS, we know experimentally that infect-
ing Asian primates with SIV or mV-2 virus DOES IN
FACT result in exactly the type of immunological sup-
pression typical of AIDS. We have the added bonus in
these experiments of producing this interesting result
with nothing more than a single virus quite similar
to the one we always find in AIDS patients with total
immune failure (and the same or almost the same virus,
in fact, as we find in West African AIDS patients). One
would think that this kind of research program would
excite skeptics who wish understanding of the nature
of this disease to come to science, but for some reason

it does not. Perhaps the reasons have to do with other
than pure logic.
In Rethinking AIDS, Root-Bernstein ironically
quotes Einstein's version of William of Occam's philo-
sophic 'razor ': 'Keep hypotheses as simple as possible,
but no simpler'. Failure to follow this maxim can be
very costly in the real world. Resources for research
are not infinite, and in practice, diversion of resources
toward experiments to test a priori epidemiologically
unlikely hypotheses can result in much wasted time and
(of course) lives lost. One can imagine, for instance,
how long-delayed might have been the program to con-
trol polio (a disease which was also, for a long time,
refractory to the 'one agent! one disease' approach crit-
icized by Root-Bernstein) had multifactorial theories
of disease been pursued on all fronts for polio paral-
ysis. As noted at the beginning of this essay, to this
day we still cannot explain why polio causes paraly-
sis in some few infected people and not most others,
but science succeeded in finding an effective preven-
tive strategy for polio paralysis long ago, nevertheless.
There is perhaps a simple lesson here.
Root-Bernstein, in the concluding paragraphs of
his book, brings us to the crux of this issue (Root-
Bernstein, 1993, p. 372): 'Assurance in science', he
writes, 'comes only through elaborating as many possi-
ble explanations as can be imagined for a phenomenon
and eliminating all that can be possibly eliminated'. A
historian of science would have inserted major qual-
ifications in such a statement. There are actually an
infinite number of possible explanations which can be
imagined for any phenomenon, and trying to eliminate
them all would leave both science and government
totally paralyzed and bankrupt. Real scientists, and the
real government agencies that fund them, need a better
plan.
In practice, only a certain relatively small segment
of possible kinds of theories are accepted or acceptable
in science, and these are based mostly on the success of
previous small classes of theories. As both evolution-
ary biologists and successful capitalist businessmen
know, no efficient search of any set of possibilities pro-
ceeds by random search of all possibilities, but rather
must succeed (if it is to succeed) by exploration of a
much more limited set of combinations (randomly cho-
sen or not) of previously successful possibilities. Major
hypotheses worthy of the expense and time of testing
in science are not generated by elaborating every pos-
sible explanation, but rather by a still quite mysterious
process of mentally narrowing down certain classes of
possible explanations to a few 'good ones'. (If there
237
were no mystery about this process, it would not be
necessary to speak of scientific 'genius').
Again: 'assurance' in science comes not from
'eliminating all possibilities that can be eliminated',
as Root-Bernstein seems to unwisely suggest, for the
resources for this do not exist in the real world. Assur-
ance in science comes from publicly testing for 'pre-
diction power' of relatively 'few' leading candidate
explanatory theories, in ways that will usefully dif-
ferentiate them from each other, and THEN finding
that one particular theory (or small class of theories)
repeatedly survives such tests.
At present, there is no getting around the fact
that the HIV-infection theory of AIDS is the leading
and most predictively successful causal hypothesis for
AIDS. Progress is thus most likely to be made by con-
tinued testing of this theory, and likely variations of
it suggested to us by various kinds of statistical evi-
dence. Testing of a causal theory of disease, of course,
is most profitably done by testing its prediction of the
occurrence of disease, or by its usefulness in prevent-
ing disease. A theory is not 'tested' by requiring that
it provides the route to a successful treatment for dis-
ease as well (again, our failure to cure either AIDS or
lung cancer does not speak to the truth or usefulness of
theories about their causation).
Allocation of resources for the testing of more rad-
ical causal theories for any disease (of which there
are, of course, an infinite number) must be made on
the basis of some prior likelihood of their being more
useful or more explanatory (our only current tests
for 'truth'), since otherwise much money would be
spent uselessly chasing moonbeams and bad guesses.
When a new causal theory 'predicts' (retrodicts) a phe-
nomenon only after the fact, and predicts it no better
than our current best theory which is much simpler
and already available for no more money, our current
theory is to be preferred. On the public level of fund-
ing, there would seem little reason to waste money
on the infinite number of alternate theories of disease
which may be more comforting than the standard one,
but which have (given current knowledge) too little
chance of being true to bet much money on. It is to this
point that we have come with AIDS.
In AIDS research, as in most research, science is
now heading generally (though never perfectly) toward
the area of investigation in which the largest number of
medical scientists and epidemiologists think maximum
payoff is most likely to lie. This is the research direction
which seems likeliest to most experts to save the most
lives. We all wish there were modifiable necessary
238
extrinsic cofactors for AIDS, but we also know that
(in keeping with a saying as old as the metaphor) if
wishes were horses, then beggars would ride. It is a
long way from postulating such modifiable co-factors
for AIDS and thinking how useful they would be if
there to actually find them.
The bottom line is that, since there are an infinite
number of such possible co-factors, those who wish
for change in research direction policy in AIDS had
best come up with better arguments for why we should
divert a great deal of our limited attention and resources
to look for things that we presently have too little rea-
son to believe may exist. Nobody cares, of course, if
a small fraction of research money is diverted to wild
ideas and bold guesses (it's impossible to keep this
from happening, actually); but survey funding is one
thing, and major policy changes are another.
In the meantime, is there any legitimate and useful
and honorable role for the scientific heretic in mat-
ters of life-or-death public policy? That depends on
whether said heretic publishes his contrary views in
scientific journals, or Spin magazine. We should note
that there is a great difference between debate within
the scientific and medical community, which may (and
must be) quite freewheeling, and the recommenda-
tions which this community should formally offer the
lay public, which ethically must emerge from a better
consensus of the best minds, and be somewhat more
conservative in nature. From the workings of Darwini-
an evolution to the workings of business and from
speaking, to writing, to work in any field of science,
there is no creative act in which the selection/editing
process is not critical. Attempts to circumvent the par-
ticular expert-review editing process which produces
progress in science certainly do not help matters. In
particular, initiating biomedical scientific debates at
the lay public level, where most chemical, immuno-
logical, and mathematical or statistical evidence for
one view versus another is bound to be lost, is to invite
public policy disaster.
I do not propose that medical treatment debates be
kept secret, only that they sometimes be left confined
to publications where those especially-well motivat-
ed lay people who work hard enough to root them
out and decode them will probably in the process also
gain enough knowledge to begin to see the data in per-
spective. Certainly, the idea of partly shielding debate
may sound patronizing, especially as it involves the
field of medicine, which has come under intense crit-
icism of late for this very flaw. And certainly, ques-
tioning authority is reasonable when one's interests
are at stake. (One is reminded of Napoleon's remark
to a famous beauty that he did not approve of women
involving themselves in political discussion, and her
reply that in a country where women were having their
heads cut off, it was natural for some of them to want
to know why).
Nevertheless, although the struggles of medicine in
this area have been especially controversial, the prob-
lem of the 'expert' does not only arise in medicine, for
we are all experts at something, and we are all igno-
rant of most things. Any expert asked for advice holds
a special obligation (knowing that the asker may not
have the time or the power to check conclusions) to edit
knowledge, and to pass along only conclusions which
are relatively sure, and which have been independent-
ly checked by other good minds. The asker trusts the
expert to do this, and indeed the essence of relationship
between the knowledge-seeker and the expert is one of
this kind of trust.
When the expertise and the advice involves a life-
or-death matter, the level of obligation and the level
of trust are amplified, and this can result in behavior
in those trained in the medical profession which may
appear more paternalistic than it is. More often, such
conservative behavior is better understood as a man-
ifestation of the wisdom, understood by responsible
adults, to refrain from saying everything one thinks
in situations where what one says really matters. The
person who gives medical advice about life-and-death
matters to the lay public in popular publications is
under an ethical obligation to refrain from pushing a
private theory with which most experts disagree, no
matter what it is (no rational person, after all, can be
so certain of private conclusions as to bet other peo-
ple's lives on them before the private theory has been
well-checked by others). Linus Pauling, to his cred-
it, probably did no harm with his popular common
cold suggestions, or probably even with this sugges-
tion to give mega-doses of vitamin C to terminal cancer
patients. The AIDS heretics, however, are in a different
ball game.
References
Curran, J.W., D.N. Lawrence & H. Jaffe, 1984. Acquired immun-
odeficiency syndrome (AIDS) associated with transfusions. N.
Eng!. J. Med. 310: 69-75.
Co1ebunders, R.. R. Ryder, H. Francis. W. Nekwei, Y. Bahwe. I.
Lebughe. M. Ndilu. G. Vercauteren. K. Nseka. J. Perriens. P.
Van der Stuyft, T.C. Quinn & P. Piot, 1991. Seroconversion rate.
mortality. and clinical manifestations associated with the receipt

of a human immunodeficiency virus-infected blood transfusion
in Kinshasa, Zaire. J. Infect. Dis. 164: 450-6.
Duesberg, P.H. (1992) AIDS acquired by drug consumption and
othernoncontangiousrisk factors. Pharmac. Ther. 55: 201-277.
Hendriks, C.M., G.P. Medley, GJ.P. van Griensven, R.A. Coutinho,
S.H. Heisterkamp & H.A.M. van Druten, 1993. The treatment-
free incubation period of AIDS in a cohort of homosexual men.
AIDS 7: 231-239. This report contains evidence that AIDS
incubation times are of the same order in homosexual men who
never received AZT or other treatment. The charges of sig-
nificant contamination by 'drug sharing' in placebo-controlled
studies are made considerably less likely by epidemiologic stud-
ies which show that AIDS risk in the era before AZT, and for
populations who received AZT as soon as requested, also show
an anti-AIDS effect, or at least no pro-AIDS effect, for AZT.
Johnson, R.E., B.L. Lawrence, B.L. Evatt, DJ. Bregman, L.D.
Zyla, J.w. Curran, L.M. Aledort, E.M. Eyster, A.P. Brownstein
& c.J. Carman, 1985. Acquired immunodeficiency syndrome
among patients attending hemophilia treatment centers and mor-
tality experience of hemophiliacs in the United States. Am. J.
Epidemiol. 121: 797-810. No slow-toxin hypothesis like Dues-
berg's explains the very sharp suddenness of the rise in mortality
in this group in 1984, nor does any toxin hypothesis explain the
initial CDC data from 1981-1984, which show incidence of total
new AIDS cases (mostly in homosexual males) rising in the typ-
ical exponential fashion of a new infectious disease spreading in
a susceptible population. Duesberg (1992, p. 252) states that this
exponential rise is probably due to an exponential rise in AIDS
testing, overlooking the fact that the mathematical relationship
held for these four years before the HIV test was available.
239
Kopec-Schrader, E., B. Tindall, J. Learrnont, B. Wylie & J. Kaldor,
1993. AZT-use does not appear to retard nor hasten AIDS in
transfusion AIDS victims. AIDS 7: 1009-1013.
Ragni, M., L.A. Kingsley & SJ. Zhou, 1992. The effect of antiviral
therapy on the natural history of human immunodeficiency virus
infection in a cohort or hemophiliacs. J. Acquir. Immune. Defic.
Syndro. 5: 120-126.AZT use is associated with slower onset of
AIDS in men with hemophilia.
Root-Bernstein, R., 1993. Rethinking AIDS. Macmillan, Inc., New
York.
Rosenberg, P.S., JJ. Goedert & R.J. Biggar, 1994. Effect of age
at seroconversion on the natural AIDS incubation distribution.
AIDS 8: 803-810. From this paper and others it is apparent
that yearly risk of progressing to AIDS is far from constant for
either persons or populations (since many populations, such as
people with hemophilia, became infected over a short period of
time). Instead, risk rises in a population almost linearly from the
date of seroconversion, for at least seven years, to peaks of as
much as 7% per year. There are a number of instances, however
(Duesberg, 1992, pp. 215, 216,227,242), when Duesbergtreats
AIDS risk -rates in infected populations as constants, such as '1-
2 % annual risk' , sometimes using the completely erroneous risk
function, resulting in the manufacture of an agreement problem
in the statistics which in reality does not exist.
Weinberg, S., 1992. Dreams of a Final Theory. Pantheon Books, New
York. This book contains the Pauli story and also an insightful
discussion of theoretical aesthetics by an acknowledged master
of scientific theory-making.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 241-270, 1996. 241
© 1996 Kluwer Academic Publishers.

How much longer can we afford the AIDS virus monopoly?

Peter H. Duesberg
Department of Molecular and Cell Biology, Stanley Hall, UC Berkeley, Berkeley, CA 94720, USA

Abstract

Until 1984 AIDS science was open. Initially the new epidemic of pneumonias and Kaposi's sarcomas, since called
AIDS, was considered a collection of non-infectious 'lifestyle' diseases. But the Centers for Disease Control
in Atlanta published that the pneumonias and Kaposi's sarcomas of male homosexuals, who were addicted to
recreational drugs, were caused by a common infectious agent because patients had been 'linked' by sexual
contacts. On the basis of the CDC's sexual linkage study, the Secretary of Health and Human Services announced
in 1984 the hypothesis that the retrovirus HlV, is the cause of AIDS. The HIV-AIDS hypothesis currently holds
a monopoly on all AIDS research and treatment. However, the HIV hypothesis is scientifically unproven. It has
failed each of 15 testable predictions, as for example that AIDS would explode via sexual transmission of HIV
into the general population. Moreover HIV meets all classical criteria of a harmless passenger virus: unpredictable
intervals between infection and any subsequent disease, and unpredictable presence and activity of the virus during
a disease. Since HIV is rare in the US, it is a marker of real AIDS risks, frequent injection of intravenous drugs,
thousands of drug-mediated sexual contacts, and transfusions. Indeed, AIDS does not meet even one of the classical
criteria of an infectious disease, as for example equal distribution between the sexes, disease within days or weeks
after infection, and exponential spread of the disease in an un-immunized population (Farr's law).
Far from being beneficial, the HIV-AIDS hypothesis has become a threat to public health in the last 10 years: It
is the sole basis for (1) the daily treatment of at least 200 000 HIV-positives with cytotoxic DNA chain terminators
originally designed to kill growing human cells for chemotherapy, like AZT, that are now prescribed as anti-HIV
drugs; (2) the clean-needle programs that encourage intravenous drug use, and the misinformation that HIV-
infection is the only health risk of recreational drug use. However, recreational drugs, such as heroin, cocaine,
amphetamines and nitrite inhalants, have long been known to have immunotoxic, cytotoxic and/or carcinogenic
effects; and (3) the anxiety and the many restrictions of human rights associated with a positive HIV-test.
Here it is proposed that American and European AIDS is caused by the long-term consumption of recreational
and of anti-HlV drugs like AZT. The drug-AIDS hypothesis correctly predicts AmericanlEuropean AIDS: (1)
AIDS is restricted to intravenous and oral users of recreational drugs and AZT; (2) AIDS is 87% male, because
males consume this share of recreational drugs; (3) AIDS occurs in newborns because mothers use recreational
drugs during pregnancy; (4) AIDS is new in America, because AIDS is a consequence of the recreational drug
use epidemic that started in the 1960s, and of AZT prescriptions that started in 1987; (5) AIDS occurs only in
a small fraction of recreational drug users, because only the highest life-time dose of drugs causes irreversible
AIDS-defining diseases -likewise only the heaviest smokers get emphysema or lung cancer; (6) AIDS manifests
as specific diseases in specific risk groups, because each group has specific drug habits. For example, pulmonary
Kaposi's sarcoma is exclusively diagnosed in male homosexuals who inhale carcinogenic alkyl nitrites; (7) AIDS
does not occur in millions of HIV-positive non-drug users, and there are thousands of HIV-free AIDS cases, because
AIDS is not caused by HIV; (8) AIDS is stabilized, even cured, if patients stop using recreational drugs or AZT
- regardless of the presence of HIV The drug hypothesis predicts that AIDS is an entirely preventable and in part
curable disease. The solution to AIDS could be as close as a very testable and affordable alternative to the HIV
hypothesis - the drug-AIDS hypothesis.
242
The emperor marched in the procession under the
beautiful canopy, and all who saw him in the street and
out of the windows exclaimed: "Indeed, the emperor's
new suit is incomparable! What a long train he has!
. .. "But he has nothing on at all, " said a little child
at last. ... "But he has nothing on at all," cried at
last the whole people. That made a deep impression
upon the emperor, for it seemed to him that they were
right; but he thought to himself, "Now I must bear up
to the end." And the chamberlains walked with still
greater dignity, as if they carried the train which did
not exist.
Hans Christian Andersen, The Emperor's New Suit
1. Fabricating the case for infectious AIDS
Hardly anybody remembers that in its first three years,
from 1981 to 1984, AIDS science was open. The
new epidemic of pneumonias and Kaposi's sarco-
mas, that was called AIDS, was considered infec-
tious by some, but many independent investigators
and even scientists from the Centers for Disease Con-
trol (CDC) in Atlanta considered AIDS behavioral dis-
eases. Recreational drugs such as nitrite and ethy1chlo-
ride inhalants, cocaine, heroin, amphetamines, phenyl-
cyc1idine, LSD, and some others were proposed by epi-
demiologists and toxicologists as the causes of AIDS
because in the early 1980s nearly all AIDS patients
were either male homosexuals who had used these
drugs as aphrodisiacs and psychoacti ve agents, or were
heterosexual intravenous drug users (Marmor et al.,
1982; Goedert et al., 1982; Jaffe et al., 1983; Mathur-
Wagh et al., 1984; Haverkos et al., 1985; Newell et al.,
1985a, 1985b; Lauritsen & Wilson, 1986; Haverkos &
Dougherty, 1988). Drugs seemed to be the most plau-
sible explanation for the restriction of AIDS to these
risk groups, because drug consumption was their only
specific common denominator - not shared with the
general population. This original drug-AIDS hypothe-
sis was called tre 'lifestyle hypothesis' (Oppenheimer,
1992).
But in April 1984 the secretary of Health and
Human Services and AIDS researcher Robert Gal-
lo from the National Institutes of Health (NIH)
announced at an international press conference in
Washington that a virus is the 'probable cause of AIDS'
(Altman, 1984). This 'AIDS virus' (Altman, 1984)
had been discovered a year earlier in France, in a
male homosexual without AIDS (Barre-Sinoussi et al.,
1983). Within two years after that announcement an
international committee of retrovirologists had named
this virus, the Human Immunodeficiency Virus (HIV),
to indicate that it was the accepted cause of AIDS
(Coffin et al., 1986).
The road for the ready acceptance of the 'AIDS
virus' by the scientific community had been paved
by epidemiologists from the CDC. By tracing sexual
contacts of male homosexual AIDS patients the CDC
claimed that it could 'link patients', who had sexual
exposure with other AIDS patients within five years of
the onset of symptoms'. (Auerbach et al., 1984). On
that basis the CDC proposed that AIDS 'may be caused
by an infectious agent that is transmissible from person
to person in a manner analogous to hepatitis B virus
infection: through sexual contacts; through parenter-
al exposure by intravenous drug abusers ... ; through
blood products; and, perhaps, through mothers who are
... intravenous drug users to their infants'. (Auerbach
et al., 1984).
However, compared to hepatitis B or any other
authentic infectious disease, the CDC's case for infec-
tious AIDS was bizarre with regard to the diversity of
the diseases linked. The CDC had 'linked by sexual
contact' the Kaposi's sarcomas of some patients to the
pneumonias of others and vice versa. The uncritical
acceptance by the scientific community of a common
infectious cause for such diametrically different dis-
eases as cancer and pneumonia allowed the CDC to
construct their case for infectious AIDS. Since cancer,
pneumonia, and by now about 30 different diseases
were all said to have the same cause, they would soon
all be called by the same new name, AIDS (Institute
of Medicine, 1988; Centers for Disease Control and
Prevention, 1992; National Institute of Allergy and
Infectious Diseases, 1994).
A second bizarre element in the CDCs case for
infectious AIDS was the assumption of an average
'latency period' from infection to AIDS of 10 months
(Auerbach et al., 1984), now 10 years (see below). The
assumption of a microbe that only causes disease after
an average latency period of 10 months was without
proven precedent. It was necessary, because prospec-
tive patients 'were asymptomatic at the time of sexual
exposure', and only developed AIDS up to 5 years
after a critical contact (Auerbach et al., 1984). Indeed,
the carriers of the assumed infectious agent had to be
exceedingly healthy during the latency period, because
they had 'large numbers' of 'approximately 250 differ-
ent male sexual partners each year'. In view of such
large numbers of sexual contacts and the long latency

periods between infection and AIDS, tracing the one
contact that would cause a disease had to be a master-
piece of epidemiological detective work. Therefore the
CDC's case for sexual transmission of AIDS was about
as compelling as the claim that one car had a flat tire at
an intersection, because another car had blown a head
gasket at the same intersection in the previous 5 years.
Nevertheless, the sexual contact study was accepted by
the scientific community as proof for infectious AIDS
without further scrutiny.
But decades later, even the CDC had lost con-
fidence in its hypothesis that clustering could prove
AIDS to be infectious: 'Such clusters may be difficult
to identify because most persons with AIDS have had
contact with many different people. In particular, drug
users and homosexual and bisexual men may have had
contact with hundreds of partners that they did not
know very well'. (Drotman, Peterman & Friedman-
Kien, 1995).
The fact that 'linked patients' 'have been frequent
users of inhaled amyl and butyl nitrite' and 'of recre-
ational drugs other than nitrite' was not considered an
AIDS risk by the CDC in 1984 (Auerbach et aI., 1984),
although CDC scientists had originally proposedrecre-
ational drugs as the cause of AIDS (Oppenheimer,
1992).
In 1984, the CDC also presented typical hemophil-
ia diseases, like pneumonia and candidiasis, as AIDS
from parenteral infection via blood transfusions - in
support of its claim that AIDS was infectious (Curran
et at., 1984; Evatt et aI., 1984; Duesberg, 1995b).
The paradox that .none of the CDC's hemophiliacs
with AIDS would have developed Kaposi's sarco-
ma from an infectious agent that presumably caused
Kaposi's sarcoma in homosexuals was effectively
hidden because all these entirely umelated diseases
had been named AIDS (Duesberg, 1992, 1994a,
1995b).
Indeed the CDC, originally established to fight
infectious diseases, had grown desperate for a new
infectious disease, because ever since polio had been
eliminated by vaccines over 30 years ago, no new
infectious diseases had plagued the Western World.
In the words of a Red Cross official, ' ... the CDC
increasingly needs a major epidemic to justify its exis-
tence' (Associated Press, 1994). Infectious AIDS, but
not the drug-AIDS hypothesis, offered such an oppor-
tunity. A new infectious epidemic readily generates
fear and funding. But research on the toxicity of recre-
ational drugs is trivial, not likely to make headlines
in the scientific literature. As a possible investment in
243
its future existence, the CDC has recently launched
a new journal, Emerging Infectious Diseases, to raise
'public awareness of exotic bugs'. (Kaiser, 1994). For
example, in 1994 the CDC promoted the Hanta virus-
after it presumably killed some Indians (Denetclaw &
Denetclaw, 1994a, 1994b) - into a threat to the nation,
and in 1995 the Ebola virus, that had apparently killed
some Zairens, was promoted into a global 'killer virus'
(Associated Press, 1995a). The CDC claimed that 108
people may have been killed by the Ebola outbreak in
Zaire in 1995 (Centers for Disease Control, 1995). But
it failed to mention that 20% of the 55 million Zairens
are Ebola virus antibody-positive, having survived the
virus without apparent disease (Dietrich J., 1995).
As AIDS claimed ever more victims and gained
ever more media attention, the CDC's message that
AIDS was a new infectious disease was enthusiasti-
cally picked up by the stars of medical research, par-
ticularly the virologists. A new infectious disease is a
magnet for virologists, microbiologists and immunol-
ogists because it holds the promise for a new microbial
pathogen and new vaccines. Since the discovery of
pathogenic microbes by Robert Koch and Louis Pas-
teur in the 1880s, the identification of a new microbial
pathogen has been the key for many brilliant careers
- like those of Walter Reed, John Enders, and Albert
Sabin. Stated the New York Times on the search for an
AIDS virus ' ... the greatest thrills for a scientist are in
discovering a new microbe, a new disease, cure and
prevention ... ' (Altman, 1992).
After decades of basic research in the War on Can-
cer, an army of highly sophisticated virologists had
failed to prove that viruses can cause cancer in humans
(Greenberg, 1986; Booth, 1988). Among these were
the current leaders of AIDS research, Luc Montagnier
from France, Robin Weiss from the U.K., David Bal-
timore, Jay Levy, Robert Gallo and even Peter Dues-
berg from the U.S. among others. Searching for other
diseases for their viruses, most cancer virologists wel-
comed AIDS as a new frontier to apply their consid-
erable skills (Duesberg, 1987; Booth, 1988; Duesberg
& Schwartz, 1992). With an AIDS virus, the medi-
cal virologists could continue their familiar research,
and their companies could extend their markets from
the narrow confines of conventional virus tests and
vaccines to the new multi-billion dollar markets of
mY-antibody tests, mv vaccines, and anti-my drugs
(Weiss & Jaffe, 1990; Duesberg, 1992).
The AIDS virus also proved to be the politically
correct cause of AIDS. No AIDS risk group could be
blamed for being infected by a God-given egalitarian
244
virus. A virus could reach all of us. Nobody would
be ostracized since 'We are all in this together'. No
so with drugs: The consumption of illicit psychoactive
drugs implies individual and social responsibilities that
nobody wanted to face.
Once accepted as the politically correct explanation
of AIDS, the HIV hypothesis has become the central
investment for a whole generation of AIDS scientists,
AIDS companies, AIDS journalists, AIDS politicians
and gay activists.
The perceived danger of an AIDS virus decimat-
ing the general public also provided the scientific and
moral arguments for quick and unreflective action and
for the complete dismissal of the competing drug-
AIDS hypothesis. The fear of nature's presumably
uncontrollable microbes created an unscientific war-
mentality that has since dominated the field (Christie,
1994). Scientists, health care workers, and journalists
would rather be safe and fast in protecting against HIV,
than sorry and slow in reflecting about the clinical and
political consequences of drug use (Lang, 1994). The
confrontation with man-made drugs, after all, would
have to take second place in urgency, as they would
not reach the innocent public.
Claiming this priority, the virus-AIDS orthodoxy
justifies intolerance, even censorship, of all those
who question infectious AIDS (San Francisco Project
Inform, 1992; Maddox, 1993a, 1993b; Cohen, 1994a;
Lang, 1994; Duesberg & Bialy, 1995). Epidemiolo-
gists from the CDC warn that to 'ignore this [HIV-
AIDS] concept would result in an unconscionable
tragedy'. (Garza, Drotman & Jaffe, 1994). Virol-
ogists are quick to call those who question the
virus-AIDS hypothesis 'irresponsible and pernicious'
(Booth, 1988; Baltimore & Feinberg, 1989). And the
New York Times still calls all non-HIV science 'cruelly
irresponsible anti-science' (Lewis, 1994).
Therefore, the 'AIDS virus' won unprecedented
popularity within a short time after its announce-
ment.
But eleven years later, in 1995, the virus-AIDS
hypothesis has still failed to produce any public health
benefits in the war on AIDS. No vaccine, no antiviral
drug, no cure, not even an effective AIDS preven-
tion have been developed. It cannot even be predicted
whether and when an infected person will get ill. And
it cannot predict which of the about 30 AIDS diseases
it will be (Duesberg, 1992; Benditt & Jasny, 1993;
Cohen, I 994a, 1994b; Wade, 1995). Moreover, the
very basis of the virus-AIDS hypothesis, the assump-
tion that AIDS is infectious, has since become ques-
tionable on several grounds. For example:
(1) Would you have believed AIDS is infectious 11
years ago, if you had known that until now not
even one of the over 400 000 doctors and health-
care workers who have treated the over 400 000
American AIDS patients since 1984 (Centers for
Disease Control and Prevention, 1994c) is con-
firmed to have contracted AIDS from a patient?
Even if that would not have changed your mind,
would you still believe in infectious AIDS if you
had considered that the health care workers were
neither protected by an anti-HIV vaccine nor by an
antiviral drug (Duesberg, 1992)?
(2) Would you have believed that a sexually trans-
mitted virus was causing AIDS if you had known
that none of the wives of the 15 000 HIV-positive
American hemophiliacs has contracted AIDS from
their husbands in the last 10 years? Their risk of
developing an AIDS-defining disease is the normal
background of these diseases in the U.S. (Dues-
berg, 1992, 1995b).
(3) Would you have believed that AIDS was conta-
gious if you had known that after a marriage of 10
years, neither the wife nor the 6-year old daugh-
ter of the late tennis star and AIDS patient Arthur
Ashe have developed AIDS or even become HIV-
positive (Ashe & Rampersad, 1993); or that the
long-term lover of the movie star Rock Hudson
has no AIDS symptoms, 10 years after Hudson
died from AIDS in 1985? Would you believe that
AIDS was sexually transmitted if you had known
that, after a 13-year marriage and 2 children, the
husband of the late AIDS patient Elizabeth Glaser
is healthy and HIV-free (Champkin, 1994)?
(4) Would you have believed in an AIDS virus if you
had known that nobody every contracted Kaposi's
sarcoma in the US from a blood donor with
Kaposi's sarcoma (Haverkos, Drotman & Hanson,
1994)?
(5) Would you have believed AIDS is a sexually trans-
mitted disease in 1984 if you had known that 11
years later there is still no AIDS in American het-
erosexuals, not even in prostitutes, unless they are
drug addicts (Duesberg, 1992)?
(6) Would you have believed in a sexually transmitted
AIDS virus if you had considered that such a virus
would be incompatible with life? Because sex is
the only known source of human life, a sexually
transmitted, fatal virus would have exterminated
itself together with its host (Duesberg, 1992).

Have we lost the war on AIDS because we have
mistaken a harmless virus for its real cause?
2. The HIV-AIDS hypothesis proves to be
unprovable
The HIV-AIDS hypothesis (Institute of Medicine,
1988; National Institute of Allergy and Infectious Dis-
eases, 1994) postulates that:
(1) HIV causes immunodeficiency by killing T-cells
(lymphocytes);
(2) immunodeficiency occurs on average only 10 years
after this virus has been neutralized by antiviral
immunity - a condition termed a 'positive HIV
test' ;
(3) immunodeficiency is the basis for about 30 pre-
viously known diseases, including pneumocys-
tis pneumonia, tuberculosis, candidiasis, Kaposi's
sarcoma, dementia, diarrhea, > 10% weight loss,
and many others (Table 1);
(4)AIDS is a sexually transmitted disease, because
HIV is a sexually transmitted virus.
Owing to the immense popularity of this hypothe-
sis, over 100 000 scientific papers have been published
on HIV since 1984. But not even one of these has
been able to explain how HIV causes AIDS. Worse
yet, not one paper exists that proves that HIV caus-
es AIDS (Duesberg, 1992; Dickson, 1994; Fields,
1994; Schoch, 1994; Thomas Jr., Mullis & Johnson,
1994).
In view of this proof-deficit, the HIV-AIDS estab-
lishment cites the 'perfect' correlation between HIV
and AIDS as support for the hypothesis that HIV caus-
es AIDS (Blattner, Gallo & Temin, 1988; Weiss &
Jaffe, 1990; San Francisco Project Inform, 1992; Mad-
dox, 1993b; Garza, Drotman & Jaffe, 1994; National
Institute of Allergy and Infectious Diseases, 1994).
However, this argument is inadequate as an element of
proof for three reasons:
(1) According to the HIV-AIDS hypothesis, the 30
AIDS-defining diseases are diagnosed as AIDS
only when antibody against HIV is present. In its
absence these diseases are called by their old name
and caused by their old causes. In other words,
AIDS is defined entirely by its hypothetical cause,
HIV. Therefore, the perfect correlation is not a nat-
ural coincidence but a perfect artefact of the defi-
nition of AIDS by its hypothetical cause, HIY. It is
one of the purest examples of circular logic.
245
(2) The HIV antibody-test for the detection of HIV is
indirect, because it does not assay for the virus.
Moreover it is not reliable; up to 90% false-
positives are obtained, depending on the subjects
tested and on the tests used (Duesberg, 1993f;
Papadopulos-Eleopulos, Turner & Papadimitriou,
1993).
(3) Even a perfect correlation is not sufficient to
prove causation. For example, perfect correlations
between yellow teeth and lung cancer, or between
hospitalization and death do not prove that one
causes the other (Duesberg, 1989, 1993d; Smith &
Phillips, 1992; Duesberg, 1993d).
In the absence of direct proof, the merit of a sci-
entific hypothesis is determined by the accuracy of its
predictions. For example, there is no direct proof for
the hypothesis that smoking causes lung cancer and
emphysema, but the prediction that long-term smok-
ing causes these diseases has validated this hypothesis.
In the following we will analyze the predictions of the
HIV-AIDS hypothesis (Duesberg, 1994a):
2.1 HN-infected persons will get AIDS, and
otherwise matched HIV-negatives will not
In the face of the relentless propaganda for the HIV
hypothesis, it comes as a big surprise to almost every-
body that there is not even one study to show that
American, heterosexual or homosexual men, who are
HIV-positive but not drug users or hemophiliacs ever
get AIDS. More precisely, there is no study to show
that such men would get AIDS-defining diseases that
exceed the long-established, low background of these
diseases in otherwise matched, HIV-free counterparts
(Duesberg, 1995a). There is not a single epidemiolog-
ical study to support the most frightening slogan of
the HIV orthodoxy; that HIV-positives develop AIDS-
defining diseases because of HIV.
All studies that claim HIV causes AIDS have
instead analyzed the AIDS risks of HIV-positive peo-
ple who were recreational drug users, were treated
with AZT or other anti-viral drugs, had received trans-
fusions, suffered from congenital diseases, or were
subject to exotic life styles as in Africa. The AIDS
risks of such groups were then determined by com-
parisons, either with normal HIV-free people or with
HIV-negative people from risk groups who were not
matched for drug use or other AIDS risks (Duesberg,
1992, 1993a, 1993c, 1993d). In other words, there
is no epidemiological evidence properly controlled for
confounding factors that HIV is a 'deadly virus' or 'the
virus that causes AIDS' .
246

Table 1. AIDS-defining diseases in the U.S. in 1992 a and 1993 a .

Immuno- 1992 1993 Non-immuno- 1992 1993

deficiencies (in %) (in %) deficiencies (in %) (in %)

<200 T-cells 79 wasting disease 20 10

pneumonia 42 22 Kaposi's sarcoma 9 5
candidiasis 17 9 dementia 6 3
mycobacterial 12 11 lymphoma 4 2
(including tuberculosis)
cytomegalovirus 8 4
toxoplasmosis 5 2
herpesvirus 5 3

Total = 61 b Total = 80 b Total = 39 Total = 20

a The data are from the Centers for Disease Control (Centers for Disease Control, 1993; Centers for Disease
Control and Prevention, 1994a).
b Over 61 % and 80% due to overlaps.

In view of the enormous experimental difficulties
and costs in sorting out the possible role HIV plays
in AIDS from the roles that recreational drugs, AZT,
transfusions, congenital diseases and exotic life styles
play, it is surprising that the assumption that HIV caus-
es AIDS has never been studied in people who are free
of confounding AIDS risks. There can only be one
plausible explanation for the absence of an epidemi-
ological study that shows that HIV causes AIDS in
people who are not in risk groups: HIV does not cause
AIDS.
Indeed, there are 1 million HIV-positive Ameri-
cans (National Institute of Allergy and Infectious Dis-
eases, 1994) and 17 million HIV-positive humans
(Merson, 1993; World Health Organization, 1995)
who are healthy, probably because they are not subject
to real AIDS risks other than the hypothetical AIDS
risk HIV Moreover, HIV-positives who stop practis-
ing risk behavior or stop being subjected to AIDS
risks even recover lost immunity - despite the pres-
ence of HIV (see below). For example, HIV-positive
hemophiliacs treated for 3 years with highly purified
blood clotting factor regained lost immunity, while
controls treated with unpurified blood products contin-
ued to lose immunity (Seremetis et aI., 1993; Dues-
berg, 1995b).
Thus HIV is only ever deadly for people who are
at risk for AIDS from toxic drugs or who depend on
long-term blood transfusions to treat underlying deadly
diseases.
2.2 American AIDS is new, because HIV is new in
America
However, in America, HIV is a long-established
retrovirus (Duesberg, 1992). Ever since the virus
could be detected in 1984, an unchanging 1 mil-
lion Americans are HIV-positive (Fig. lA) (Curran
et al., 1985; National Institute of Allergy and Infec-
tious Diseases, 1994; Farber, 1995b). By contrast, a
new microbe/virus spreads exponentially in a suscep-
tible population (see Section 5). Thus the non-spread
of HI V establishes it as an old virus in America (Dues-
berg, 1992).
2.3 HIV is active and abundant in persons with AIDS,
and inactive and rare in healthy virus carriers
All microbes cause diseases by killing or alterating a
larger number of target cells than the host can spare or
regenerate during the course of an infection. Thus HIV
would have to infect and kill at least 50% of all human
T-cells to cause AIDS.
However, in AIDS patients HIV is found hiber-
nating in only 0.1 % of T-cells, and biochemically
active in less than 0.01 % of T-cells (Duesberg, 1992;
1993e; Piatak et al., 1993). Indeed, there are healthy
HIV-positive people with 30- to 40-times more infect-
ed T-cells than in AIDS patients (Simmonds et al.,
1990; Bagasra et al., 1992; Duesberg, 1992). The
fact that the vast majority of susceptible T-cells remain
uninfected, even in people dying from AIDS, is the
definitive evidence that there is no active HIV in
HIV-antibody-positive persons. HIV is neutralized by
 247
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Year Year

Fig.lA. mY-AIDS correlation in the U.S. since 1981. Fig. lB. Cocaine and heroine epidemics in the U.S. since 1980.

antiviral immunity, even in AIDS patients. If there
were un-neutralized mv, all T-cells would be infect-
ed.
The fundamental problem for the HIV-hypothesis
is not just how mv works, but how it causes fatal
diseases when it does not work at all. Since there is no
rational explanation for how mv could cause AIDS,
HIV researchers now postulate a multiplicity of indi-
rect mechanisms of pathogenesis (Blattner, Gallo and
Temin, 1988; Booth, 1988; Gallo, 1991; Maddox,
1991, 1993b; Maddox, 1995; Wain-Hobson, 1995;
Weiss et al., 1992; Wade, 1995).
2.4 HN causes AIDS by killing T-cells
However, viruses that integrate their genomes with
that of the host, like mv, cannot kill the host cell.
Since the genes of such viruses are part of the host's
genes, integrated viruses can only replicate as long
as the host survives integration and remains able to
express integrated viral genes. All integrated viruses
survive from passive and retroviruses also from active
replication with the host. This strategy only works
if the host survives integration. If the virus were to
kill the cell as it is integrated, integration would be a
useless exercise and it would be undetectable. Indeed,
mv is mass-produced for the 'HIV test' in immortal
T-cell lines in cell culture at titers of 106 infectious
units per ml (Rubinstein, 1990; Karpas et aI., 1992).
Luc Montagnier the discoverer of mv, and many other
researchers have confirmed that mv does not kill T-
cells (Lemaitre et al., 1990; Duesberg, 1992).
2.5 Since the generation time of HN is two days, HN
will cause AIDS two weeks after infection
The mY-hypothesis predicts AIDS within 2 weeks
after infection, because mv, like all other retrovirus-
es, replicates within two days. During that time one
infected cell produces at least 100 new viruses (Weiss
et al., 1985). In the absence of antiviral immunity, these
100 viruses would in turn infect 100 cells producing
100 x 100 or 104 infected cells within 4 days after
infection. Within 14 days of such exponential growth,
104 cells - the equivalent of a human body - would
be infected. This is the typical latent period of proven
pathogenic retroviruses, like Rous sarcoma virus, and
of pathogenic human viruses like fiu, measles, mumps,
chicken pox, and herpes, which all have generation
times like HIV (Fenner et al., 1974; Mims & White,
1984).
However, if dated from the time of mv infection,
AIDS occurs at totally unpredictable times. The latent
period between infection and AIDS was estimated to
248
average 10 months in 1984 (Auerbach et al., 1984), 10
years in 1988 (Institute of Medicine, 1988) and over 20
years in HIV-positive hemophiliacs in 1994 (Phillips
et al., 1994). A Berkeley mathematician recently has
determined the most accurate formula for the latent
period of HIV, by subtracting 1984, the year when
HIV was proposed to cause AIDS, from the current
calendar year. But blaming AIDS on a HIV infection
that occurred 10 years earlier is the logical equivalent
of blaming today's broken leg on stumbling over a
crack in the sidewalk 10 years ago.
2.6 Viral AIDS will spread exponentially
('explode')
The AIDS orthodoxy has predicted that according
to Farr's law (Bregman & Langmuir, 1990), AIDS
would spread exponentially ('explode') into the gen-
eral, unimmunized population (Duesberg, 1992) - just
like all other new infectious diseases.
However, AIDS in America and Europe remained
confined to the original risk groups, i.e. ma1e homo-
sexuals practicing risk behaviour and intravenous drug
users (National Commission on AIDS, 1991; Centers
for Disease Control and Prevention, 1994). Instead of
growing exponentially, AIDS in America (and Europe)
has increased slowly, over 15 years, far from reaching
saturation of the susceptible population of over 100
million sexually active adults (Fig. IA). AIDS behaved
just like an occupational disease.
2.7 The spread ofAIDS will parallel the
dissemination of HIV
However, there is no correlation between the spreads
of AIDS and HIV in America. In the last 10 years,
AIDS increased in America from a few hundred to
about 100 000 cases annually (Fig. IA) (Centers for
Disease Control and Prevention, 1994c). (The burst of
AIDS cases in 1993 is largely an artefact of the most
recent redefinition of AIDS, which nearly doubled the
AIDS cases in one year (Centers for Disease Control
and Prevention, 1994c».
However, during those same 1a years HIV did
not spread at all (Fig. lA). Ever since HIV became
detectable in 1985, an unchanging one million Amer-
icans have been HIV-positive up to 1994 (Fig. lA)
(Duesberg, 1992, 1994a; National Institute of Allergy
and Infectious Diseases, 1994). To hide this discrep-
ancy, a latency period of 10 years has been postulated
between HIV and AIDS.
2.8 Like all other sexually transmitted diseases, AIDS
in America will equilibrate between the sexes
However, since 1981, AIDS has remained in the orig-
inal risk groups in America, i.e. in male homosexuals,
in intravenous drug users of which over 75% are males
(Duesberg, 1992), and hemophiliacs which are nearly
all males. Since 1981,347767 out of 401749, or 87%
of all American AIDS cases, have been males (Centers
for Disease Control and Prevention, 1994c).
2.9 HIV is a sexually transmitted virus
However, HIV could never survive in evolution from
sexual transmission. Based on studies of discordant
couples, e.g. hemophiliacs with HIV and spouses with-
out, conducted by the CDC and others, it takes on
average 1000 unprotected sexual contacts to transmit
HIV (Hearst & Hulley, 1988; Peterman et al., 1988;
Rosenberg & Weiner, 1988; Lawrence et al., 1990;
Blattner, 1991). According to Rosenberg and Weiner,
'HIV infection in non-drug using prostitutes tends to
be low or absent, implying that sexual activity alone
does not place them at high risk'. The efficiency of
transmission in homosexual contacts is also estimated
at 1 in 1000 contacts (Jacquez, 1994).
Since about 10 to 30 sexual contacts are required
to generate a child, but 1000 contacts are required to
transmit HIV, HIV could never survive natura1 selec-
tion on the basis of sexual transmission, because the
host would outgrow the parasite. Conventional vene-
real microbes, like syphilis and gonorrhoea, survive
because they are transmitted by about two sexual con-
tacts (Freeman, 1979). HIV also could not survive from
transmission to newborns if it were fatally pathogenic
to babies, as is claimed by the proponents of the HIV
hypothesis (Blattner, Gallo & Temin, 1988; Institute
of Medicine, 1988).
The extremely low efficiency of sexual transmis-
sion of HIV also predicts that the safe-sex campaigns
conducted by the HIV orthodoxy will be of very lim-
ited value. Only those would benefit who either have
on average 1000 sexual contacts with HIV positives
or those who have on average 250 000 contacts with
average Americans, of which only 1 million in 250
million is HIV positive (Fig. lA) (Duesberg, 1992;
National Institute of Allergy and Infectious Diseases,
1994).

2.10 AIDS will be restricted by controlling sexual
transmission of HIV via 'safe sex', and parenteral
transmission of HIV via 'clean needles'
But AIDS continues to increase steadily despite the
'safe sex' and 'clean needle' programs (Centers for
Disease Control and Prevention, 1994c) (see Fig. lA).
2.11 Health-care workers will contract AIDS from
their patients, scientists from propagating virus, and
prostitutes from their clients
Not a single confirmed case exists in the scientific lit-
erature of a health-care worker who contracted AIDS
(Duesberg, 1992, 1994a) from one of the over 400 000
American AIDS patients (Centers for Disease Control
and Prevention, 1994c). None ofthe tens of thousands
of HIV researchers have developed AIDS from prop-
agating HIV. And no prostitutes picked up AIDS from
their clients - despite the absence of antiviral vaccines
or effective anti-HIV drugs (Duesberg, 1992, 1994a).
A few unpublished cases have been claimed, but each
of these seemed to have been treated with the cytotoxic
drug AZT that is sufficient to cause immunodeficiency
(see below) (Cohen, 1994a).
2.12 Chimpanzees inoculated with HN will develop
AIDS, and the 15 000 American hemophiliacs who
were infected by transfusions before 1984 will die
from AIDS
Not one of the 150 chimpanzees inoculated with HIV
since 1983 has developed AIDS (Duesberg, 1992).
Contrary to prediction, the median life of American
hemophiliacs has increased 2.5-fold from 11 to 27
years between 1972 and 1987 (Institute of Medicine,
1988; Stehr-Green et al., 1989), although 75% (15000)
were infected with HIV by transfusions received before
1984 (Duesberg, 1992). However, in 1987 the median
life of HIV-positive hemophiliacs started to decrease
again (Chorba et at., 1994) because since then they
have been treated with the cytotoxic AZT (Duesberg,
1995b) (see below).
2.13 Natural or vaccine-induced anti-HIV immunity
will cure AIDS or protect againstfuture AIDS
Natural antiviral immunity, a positive HIV-test, is
observed in many AIDS patients, but does not pro-
tect against AIDS. Paradoxically, anti-HIV immunity
is by HIV-AIDS definition the only criterion to predict
who gets AIDS. With all other viruses and microbes
- there is no exception - immunity is the only criteri-
249
on to predict who does not get a disease. It is for this
reason that antiviral/microbial immunity is artificially
induced by vaccination. It is also for this reason that
the HIV-AIDS establishment has called for an HIV
vaccine since 1984.
2.14 All AIDS diseases are consequences of
HN-mediated T-cell deficiency
Indeed, up to 1992 about 61 % of all American AIDS
diseases, the microbial diseases such as Pneumocystis
carinii, candida, tuberculosis, etc. were consequences
of Acquired Immuno Deficiency (Table 1) (Centers for
Disease Control, 1993).
However, 39% were neither caused by, nor con-
sistently associated with, immunodeficiency. These
include Kaposi's sarcoma, lymphoma, >10% weight
loss, and dementia (Table 1). Accordingly, Kaposi's
sarcoma and dementia have been diagnosed in male
homosexuals whose immune systems were normal
(Murray et at., 1988; Spornraft et at., 1988; Gill et at.,
1989; Friedman-Kien et aI., 1990; Duesberg, 1992;
Kaldor et at., 1993; Bacellar et at., 1994).
In 1993, the CDC introduced, once more, a new
AIDS definition (Centers for Disease Control and Pre-
vention, 1992). This has shifted the balance ofimmun-
odeficiency to non-immunodeficiency AIDS diseases
significantly in favour of immunodeficiency diseases,
i.e. from 61 % to 80% (Table 1) (Centers for Disease
Control and Prevention, 1994a). The critical innova-
tion of this new definition was that a healthy person
with less than 200 T-cells, but with no clinical dis-
ease, would now be registered as an AIDS patient. The
new AIDS definition nearly doubled the new AIDS
cases, thus adding new life to the sagging curves
of the American AIDS statistics (Fig. lA). Howev-
er, if one subtracts from the 1993 statistics the new
AIDS cases with less than 200 T-cells, the ratio of the
remaining real immunodeficiency diseases to the non-
immunodeficiency diseases is almost the same as in
1992.
Imagine the rationalisations an unprejudiced virol-
ogist, who is a)'Vare of heterogeneity of AIDS-defining
diseases, must make to accommodate an AIDS virus.
Ever since Koch and Pasteur, microbiologists and
virologists were taught that a specific microbe or virus
would cause a specific disease - e.g. polio, flu, measels,
chicken pox, hepatitis, etc. - just like a particular musi-
cal instrument would make specific sounds.
To accommodate the AIDS virus, the concept of a
specific microbe causing a specific disease had to be
250
abandoned for the following bewildering scenario: By
picking up the AIDS virus from a diarrhea patient,
a person would get Kaposi's sarcoma. The Kaposi
patient would then be able to cause dementia or pneu-
monia in others by passing on the diarrhea virus, just
as the CDC's sexual contact study had claimed in
1984 (Auerbach et aI., 1984). As of 1993, anyone
of these patients could have also caused a clinically
undetectable depletion of T-cells in others, again by
passing on their diarrhea, dementia, Kaposi's sarcoma
and pneumonia virus.
Moreover, the unprejudiced virologist would have
to reconcile this bewildering pathogenic potential of
HIV with the fact that HIV is one of the most primi-
tive viruses in terms of genetic information that exists,
carrying only 9000 nucleotides. This is the viral equiv-
alent of a musical instrument that is said to sound like
an orchestra, although it only has the repertoire of a
bell.
2.15 If HIV is the cause of AIDS, the percent
incidence ofAIDS diseases will be the same in all risk
groups
However, the percent incidence of AIDS-defining dis-
eases is very different in different risk groups. For
example, Kaposi's sarcoma in America and Europe
is almost exclusively observed in male homosexuals
(Beral et aI., 1990). Intravenous drug users have a pro-
clivity for tuberculosis, weight loss, and pneumonia
(Duesberg, 1992) and a very high mortality, dying at
30 years (Lockemann, 1995). Pneumonia and candidi-
asis are virtually the only AIDS disease ever diagnosed
in hemophiliacs (Duesberg, 1992; Duesberg, 1995b).
And bacterial infections other than tuberculosis are
almost exclusively diagnosed in babies with AIDS
(Centers for Disease Control, 1987; Centers for Dis-
ease Control and Prevention, 1992; Duesberg, 1992).
Thus the percent incidence of an AIDS disease is very
different in different AIDS risk groups.
In view of this, some AIDS researchers cite co-
factors of HIV, such as recreational drugs and immuno-
suppressive transfusions, as explanation for risk group-
specific diseases (Evans, 1989; Duesberg, 1992; Lud-
lam, 1992; Root-Bernstein, 1995a). However, they fail
to provide evidence that such cofactors depend on the
cofactor HIV to be pathogenic.
The CDC and other mainstream AIDS researchers
insist that recreational drugs and transfusions solely
enhance the risk to get infected by HIV, rather than
playing causative roles in AIDS (Cohen, 1994a). It
is for this reason that the CDC refers to drug- or
transfusion-risk groups as 'exposure categories' (Cen-
ters for Disease Control and Prevention, 1994a). In
fact, the CDC obscures the existence of risk-group-
specific AIDS diseases by reporting only the percent
incidence of AIDS diseases in all risk groups com-
bined (Centers for Disease Control and Prevention,
1994a).
It is evident that the HIV-AIDS hypothesis is unable
to make even one verifiable prediction - the hallmark
of a failed hypothesis.
Even if a hypothesis fails to make valid predictions
in terms of established scientific criteria, it could by
chance lead to a valid prevention or treatment. But the
HIV-AIDS hypothesis has not lead to any public health
benefit. Instead it has harmed not only AIDS patients
but also healthy persons who are at risk of AIDS or
just antibody-positive (see Section 6).
3. HIV - a harmless passenger virus
Confronted with the evidence that the HIV-AIDS
hypothesis has failed to make valid predictions and
failed to lead to public benefits, many agree that HIV
may not cause AIDS. But then, they wonder: What
does HIV do?
Indeed, all viruses are generally assumed to be
pathogenic by an unsuspecting public, because a few
of them actually are. Likewise, a whole nation is often
stereotyped by the characteristics of a minority. For
example the French are considered great lovers and the
Italians great singers, because a few of them are great
lovers and singers. The same is true for viruses.
In reality, most viruses cause no disease at all.
Viruses are not here to kill their hosts, not even to
cause disease. Instead, viruses are here for exactly the
same reasons we are, to continue their species. This
goal can only be achieved by keeping the host species
alive, and it is achieved best if every host survives the
infection. That is the reason that most viruses never
cause a disease in their host. Therefore they are called
passenger viruses. Passenger viruses are those that take
a ride on the host, but demand no more from the host
than a passenger demands from an airplane.
Since HIV is not the cause of AIDS, the simplest
and most plausible HIV hypothesis postulates that HIV
is just a passenger virus (Duesberg, 1994a). A passen-
ger virus is defined as follows:
(1) The time of infection is irrelevant to the onset of
any disease.

(2) The passenger virus can be either active or passive,
either rare or abundant during any disease.
(3) The passenger virus can be entirely absent during
any disease.
(4) If the passenger virus is de-repressed by a fail-
ing immune system, as for example during a dis-
ease, the passenger virus mayor may not contribute
to the disease. For example HHV-6 (Cone et al.,
1994) or cytomegalovirus may contribute their spe-
cific pathogenic properties to an immunodeficient
patient.
HIV meets all these criteria with regard to its rela-
tion to AIDS:
(1) HIV infects at totally unpredictable times prior to
or even after the onset of AIDS (see below) or not at
all (Duesberg, 1992; Phair et al., 1992; Duesberg,
1993f).
(2) HIV is typically passive and rare during AIDS -
hence the notorious difficulties of leading AIDS
researchers in isolating HIV from AIDS patients
(Duesberg, 1992).
(3) There are thousands of HIV-free AIDS cases, e.g.
HIV-free homosexuals with Kaposi's sarcoma and
HIV-free intravenous drug users with tuberculosis
(Duesberg, 1993f).
(4) There is no report in the literature that AIDS
patients are clinically distinguishable from each
other because HIV is active or passive or not
present at all (Duesberg, 1993b; Duesberg, 1994a).
Thus HIV is a harmless passenger virus, even when
it is active in some rare immunodeficient persons
(Duesberg, 1993e).
If this is true, there should be many more HIV
carriers than AIDS patients. Indeed, there are 1 mil-
lion healthy HIV-positive Americans (Dues berg, 1992;
Duesberg, 1994a) and there are 17 million healthy HIV-
positive humans (Merson, 1993; National Institute of
Allergy and Infectious Diseases, 1994; World Health
Organization, 1995).
Nevertheless, there is some tenuous evidence that
HIV can function as an autonomous pathogen, caus-
ing a mild fiu-like or mononucleosis-like condition,
prior to antiviral immunity (Albert et al., 1987; Dues-
berg, 1987; Kessler et al., 1987; Gaines et aI., 1988;
Marcus and the CDC Cooperative Needlestick Surveil-
lance Group, 1988; Tindall et al., 1988; Pedersen et
al., 1990; Duesberg, 1992; Niu, Stein & Schnittmann,
1993). However, in millions of HIV-positives HIV
infection has gone unnoticed, because they do not
experience a characteristic HIV-disease prior to anti vi-
251
ral immunity -like measels, mumps or fiu occur prior
to immunity against these viral infections.
The rare cases in which HIV infections prior to
antiviral immunity have been linked with mononucle-
osis or fiu-like symptoms are restricted to prospective
studies of male homosexuals at risk for AIDS. These
cases could either be coincidences with a common cold
or with intoxications from recreational drug use (see
below) (Gaines et al., 1988; Tindall et al., 1988; Peder-
sen et at., 1990) rather than evidence for HIV disease.
4. HIV - a marker for AIDS risks
Even those who understand all virological arguments
against HIV as the cause of AIDS, and for HIV as a
passenger virus, have misgivings about dismissing the
HIV-AIDS hypothesis, because HIV is more common
in AIDS patients than in the healthy popUlation. This
sounds like an ominous connection, but only if it is
taken out of its trivial microbiological context.
This trivial context is that AIDS risk behaviour is
synonymous with collecting microbes. The common
denominator of all AIDS risk groups in America and
Europe is that they collect microbes either from unster-
ile drugs injected with unsterile equipment, or from the
thousands of drug-mediated sexual contacts, that are
required to transmit HIV sexually, or from transfu-
sions received for the treatment of illnesses (Jaffe et
at., 1983; Auerbach et al., 1984; Lauritsen & Wil-
son, 1986; Haverkos & Dougherty, 1988; Rappoport,
1988; Adams, 1989; Callen, 1990; Lifson et at., 1990;
Archibald et at., 1992; Duesberg, 1992; Jones, 1994;
Mullis, 1995). This is the reason that numerous uncom-
mon microbes are common not only in AIDS patients
but also in healthy persons from AIDS risk groups.
For example, the bacteria that cause syphilis, gonor-
rhea, and tuberculosis, the hepatitis virus, rare strains
of herpes virus, putative leukemia virus, genital papil-
loma virus, and even HIV are all common in AIDS
risk groups and AIDS patients but uncommon in the
general population (Duesberg, 1992). Thus HIV is just
one of many microbial markers of AIDS risk behavior.
Since AIDS is defined as one of 30 diseases in the pres-
ence of HIV, rather than any other microbial or viral
marker, the correlation between HIV and AIDS is in
theory 100%.
252
S. The myth of infectious AIDS - unconfirmed
If a hypothesis is unproductive, and unable to make
verifiable predictions, the scientific method calls for
alternative hypotheses. To find the correct AIDS
hypothesis, we need to decide first whether to look
for other viruses and microbes or for drugs as causes
of AIDS. In other words, we need to know whether
AIDS is infectious or not.
There are five classic criteria to define an infectious
disease.
In individuals:
(1) The causative microbe/virus is abundant and very
active in target tissues during the course of the
disease.
(2) The disease follows within days or weeks after
infection, because microbes/viruses multiply expo-
nentially with generation times of 0.5 to 48 h unless
they are stopped by immunity (see above).
In populations:
(3) The disease spreads, according to Farr's law, expo-
nentially in an un-immunized population within
weeks or months, and subsequently fades away as
antiviral immunity builds up (Bregman & Lang-
muir, 1990). The bell shaped curve of a seasonal
flu epidemic is the model.
(4) Infectious diseases are equally distributed between
the sexes.
(5) Infectious diseases are most commonly observed
in those under 20 and over 60 years of age. This
is because after birth the immune system builds up
a wide repertoire of antimicrobial resistances that
is nearly complete at 20, and over 60 the system
begins tq decline.
But American/European AIDS does not fit one of
these criteria:
(1) There is no abundant microbe common to all Amer-
ican AIDS cases. If HIV is present, it is typically
rare and hibernating.
(2) If dated from the time of HIV infection, AIDS
occurs at entirely unpredictable times ranging from
less than 1 year to over 10 years or never. It has
now been 10 years since 1 million Americans were
found to be HIV-infected. Most of these and 17
million healthy, HIV-positive non-Americans are
still waiting for HIV to cause AIDS.
(3) American AIDS has slowly increased over 10
years. Although AIDS affects annually only a small
fraction of susceptible persons - less than 100 000
out of a susceptible pool of 250 million Ameri-
cans - it has now almost plateaued for 4 years
[after adjusting for new additions of diseases to
the AIDS definition] (Centers for Disease Control
and Prevention, 1994b). Thus AIDS in America
has increased steadily over years, just like an occu-
pational disease, as for example lung cancer from
smoking. There is no evidence for immunity and
no evidence for a bell shaped AIDS curve.
(4) American AIDS is 87% male (Centers for Disease
Control and Prevention, 1994c), which is epidemi-
ologicallyas far from equality between the sexes as
the sun is from the earth. A similar sexual bias has
been observed early in the epidemic of smoking-
related diseases in the 1960s, before women picked
up smoking at the same rate as men.
(5) 98% of all American AIDS cases are over 20 and
under 60 (Centers for Disease Control and Preven-
tion, 1994c). Only 1% each are under 20 and over
60! Such an age bias is typical of occupational
diseases, like bullet wounds for soldiers.
Thus AIDS in America and Europe (Duesberg,
1992) does not meet even one of the criteria of infec-
tious disease.
Indeed, even proponents of the HIV-AIDS hypoth-
esis, such as Jaap Goudsmit from University of Ams-
terdam, grant that 'AIDS does not have the charac-
teristics of an ordinary infectious disease. This view
is incontrovertible' (Goudsmit, 1992). The AIDS epi-
demiologists Eggers and Weyer from the University of
Cologne state that 'the spread of AIDS does not behave
like the spread of a disease that is caused by a single
sexually transmitted agent' (Eggers & Weyer, 1991).
To reconcile AIDS with infectious disease they 'sim-
ulated a cofactor [that] cannot be identified with any
known infectious agent'. The epidemiologists Ander-
son and May from the University of London had to
invent 'assortative scenarios' for different AIDS risk
groups to match AIDS with infectious disease (Ander-
son & May, 1992).
Until we have scientific evidence, infectious AIDS
is just a myth - and, in view of the facts, a very implau-
sible myth indeed.
6. The HIV-AIDS hypothesis is costly,
unproductive and harmful
For 11 years now the world has fought the war on
AIDS united by the HIV-AIDS hypothesis. But despite
its enormous popularity, the virus-AIDS hypothesis
has been a complete failure in terms of public health
benefits: no vaccine has been developed that prevents

AIDS, no drug that cures AIDS, no policy that stops
the spread of AIDS (Benditt & Jasny, 1993; Fields,
1994; Swinbanks, 1994; Wade, 1995).
Whatever the reasons are for the complete failure
of the HIV-AIDS hypothesis to produce public health
benefits, one thing is clear: it was not for lack of try-
ing. The passionate complaint of Shilts' 1987 book,
And the Band Played On, that indifference was the
only obstacle against a solution of AIDS (Shilts, 1987),
has long become profoundly obsolete. Since 1984, an
unprecedented $35 billion has been paid by the US
taxpayer alone in support of HIV-AIDS research and
treatment - more than for all other viral and microbial
diseases combined (AIDS Weekly, 1995; Gutknecht,
1995; Henry, 1995; Stone, 1995). With all this spend-
ing, more research has been done on HIV than on any
other virus in history, but absolutely no progress has
been made against AIDS. Time, at least, has voted
against the HIV-hypothesis. Traditionally, such com-
plete failures are the consequence of a flawed hypoth-
esis.
But the HIV-AIDS establishment does not only cost
dearly and fails to produce positive results, it also caus-
es irreparable (1) clinical, (2) educational, and (3) psy-
chological damage:
(1) Clinical damage. World-wide about 200 000 HIV-
antibody positive persons are prescribed, every six
hours, the highly toxic DNA chain terminator AZT or
equivalents like ddI, ddC, and d4T as anti-HIV drugs
(Duesberg, 1992; Thomas, 1995). Most of these, ie.,
200 000 minus the 50 000 to 80 000 annual AIDS
patients in America and Europe, are healthy HIV-
positives given AZT to prevent AIDS. Recently these
include even unborn American and French children
and their HIV-positive mothers, although the risk of
such children to pick up HIV from their mothers is only
about 25% (The Lancet, 1994; Farber, 1995a).
AZT was designed 30 years ago to kill grow-
ing human cells for cancer chemotherapy (Horwitz,
Chua & Noel, 1964; Duesberg, 1992). In view of its
inevitable toxicity, AZT was approved as an anti-HIV
drug only tentatively in 1987 (Kotala, 1987). See the
warnings of a non-medical manufacturer, Sigma, on
the label of an AZT bottle (Fig. 2). The label points
out, with skull and crossbones, AZT's toxicity to the
bone marrow, the source of T-cells.
Indeed, AZT therapy of HIV appears harmful and
irrational. Since HIV is postulated to cause AIDS by
killing T-cells (see above), it is irrational to kill the
same HIV-infected cells twice - once with HIV and
253
again with AZT. Moreover, it is harmful to kill numer-
ous uninfected cells with AZT collaterally (Kola-
ta, 1987; Lauritsen, 1990; Nussbaum, 1990; Wyatt,
1994).
Accordingly, AZT has failed to cure even one
AIDS patient or to prevent AIDS in HIV-infected per-
sons (Duesberg, 1992; Oddone et al., 1993; Tokars
et al., 1993; Bacellar et al., 1994; Goedert et al.,
1994; Lenderking et al., 1994; Seligmann et al.,
1994). Instead, evidence is growing that AZT caus-
es AIDS-defining and other diseases as expected from
a chain terminator of DNA synthesis (see below) (Mir
& Costello, 1988; Lauritsen, 1990; Duesberg, 1992;
Lauritsen, 1992; Bacellar et ai., 1994; Cohen, 1994a;
Duesberg, 1994a; Goedert et al., 1994; Lewis-Thorton,
1994).
To hide the emerging tragedy, the HIV-AIDS estab-
lishment tries to trivialize the only known effects of
AZT, its cytotoxicity (cell-killing ability) (Physicians'
Desk Reference, 1994). Yet this evidence is either
denied or belittled by the AIDS establishment as the
following examples document:
(i) The observation that 'HIV dementia among
those reporting any antiretroviral use (AZT, ddI, ddC,
or d4T) was 97% higher than among those not using
this antiretroviral therapy' is interpreted by its authors
with little concern for percentages: 'This effect was
not statistically significant' (Bacellar et al., 1994).
Goedert et al. explain their stunning results -
that HIV-positivehemophiliacs on AZThave 4.5-times
more AIDS and have a 2A-times higher mortality than
untreated HIV-positive hemophiliacs - by saying this
happened 'probably because zidovudine was adminis-
tered first to those whom clinicians considered to be at
highest risk' (Goedert et ai., 1994).
(ii) Saah et al. explain their observations that male
homosexuals on AZT have a two- to four-fold higher
risk of Pneumocystis pneumonia than untreated con-
trols as follows: 'Zidovudine was no longer significant
after T-helper lymphocyte count was considered, pri-
marily because nonusers had higher cell counts ... '
(Saah et ai., 1995). The fact that an inhibitor of DNA
synthesis designed to kill human cells would inhibit
lymphocyte growth was not mentioned.
(iii) The blunt result that AZT prophylaxis reduced
survival from 3 to 2 years, and caused 'wasting syn-
drome, cryptosporidiosis, and cytomegalovirus infec-
tion ... almost exclusively' in AZT-treated AIDS
patients, was interpreted like this: 'The study of
patients who progress from primary HIV infection
to AIDS without receiving medical intervention gives
 -
254
100 me A-2169 Lot 92H78011
~~..-.:")
(AZTi Azidothymidine)
Desiccate
Store at less than O·C
Fig. 2. The label on an AZr bottle from the Sigma Co. The AZT advisory on the label reads: 'TOXIC. Toxic by inhalation. in contact with skin
and if swallowed. Target organ(s): Blood bone marrow. If you feel unwell. seek medical advice (show the label where possible). Wear suitable
protective clothing.'
insights into the effects of medical intervention on pre-
sentation and survival after developing an AIDS defin-
ing illness' . But the nature of these 'insights' was not
revealed by the authors (Poznansky et aI., 1995).
(iv) The largest test of AIDS prophylaxis with AZT
of its kind, the Concorde trial, found a 25 % higher mor-
tality in AZT recipients than in untreated controls. In
view of this Seligmann et al. reached the conservative
conclusion: 'The results of Concorde do not encour-
age the early use ofzidovudine [AZT] in symptom-free
mY-infected adults' (Seligmann et aI., 1994).
(v) Five years after introducing AZT prophylaxis
to several hundred thousands of healthy mY-positives,
Paul Volberding of the University of California at San
Francisco, Anthony Fauci of the National Institute of
Allergy and Infectious Diseases and over 100 scientific
collaborators now publish in the New England Journal
ofMedicine: 'Zidovudine ... does not significantly pro-
long either AIDS-free or overall survival. These results
do not encourage the routine use of Zidovudine (Vol-
berding et al., 1995)'. In an accompanying editorial
'Time to hit mv, early and hard' the 'Journal' makes
the forward recommendation to treat HIV infection
with AZT and other experimental drugs before antivi-
ral immunity restricts the virus to chronic latency (Ho,
1995). The article suggests that current AZT prophy-
laxis is too little too late. This is said although the
ineffectiveness of the proposed 'early and hard' treat-
ment is known since 1993 (Tokars et aI., 1993).
(vi) The occurrence of 8 serious birth defects,
8 spontaneous abortions and 8 therapeutic abortions
among 104 pregnancies treated with AZT is interpret-
ed as 'not proving safety, thus lending tenous support
to the use of this drug'. (Kumar, Hughes & Khurranna,
1994).
==
~
=
/30516417.1/
C, " N,O, FW 267.2
Punty > 99% (HPlC) --
--
.."..,
AZT must be considered the most toxic among legal
public health threats available to healthy persons. much
more toxic than alcohol and tobacco. For this reason
I have termed AZT AIDS by prescription (Duesberg,
1992). Even Burroughs Wellcome, the manufacturer
of AZT, makes the same assessment, but expresses
it in different words: 'It is often difficult to distin-
guish adverse events possibly associated with zidovu-
dine [AZT] administration from underlying signs of
mv disease ... ' (Physicians' Desk Reference, 1994).
(2) Educational damage. Since mv, but not drugs, is
thought to cause AIDS, the mY-AIDS establishment
educates the public to use 'clean needles' for the injec-
tion of unsterile (!) street drugs and to wear condoms
for sex under the influence of aphrodisiac drugs (Insti-
tute of Medicine, 1988; San Francisco Project Inform,
1992; Benditt and Jasny, 1993; National Institute of
Allergy and Infectious Diseases, 1994). However, the
disregard, in fact explicit dismissal, of drug toxicity by
the AIDS establishment (Weiss & Jaffe, 1990; Asch-
er et al., 1993; Duesberg, 1993d; Maddox, 1993a;
Schechter et al., 1993c; Cohen, 1994a) encourages
recreational drug use because it eliminates the fear
of drug toxicity. A popular joke illustrates this point:
'Two junkies are reminded by a friend not to share
a syringe full of cocaine. Their response: 'We wear
condoms and use a clean needle' . '
Yet long-term use of recreational drugs, including
cocaine, heroin, amyl- and isobutyl nitrite inhalants,
amphetamines, and others has been documented in
numerous studies to cause exactly the same diseases
that are now blamed on HIV (Haverkos & Dougherty,
1988; Stoneburner et aI., 1988; Lerner, 1989; Dues-
berg, 1992). The list of drug-induced diseases, estab-
lished long before the discovery of mv, reads like

a catalogue of AIDS-defining diseases: weight loss,
fever, dementia, tuberculosis, oral thrush, pneumonia,
diarrhea, mouth infections, night sweats, and many
others (see below) (Lerner, 1989; Duesberg, 1992).
(3) Psychological damage. According to the HIV-
AIDS establishment, nearly all HIV-infected, healthy
persons are claimed to die from AIDS on average 10
years after infection by HIV (Institute of Medicine,
1988; Garza, Drotman & Jaffe, 1994, National Insti-
tute of Allergy and Infectious Diseases, 1994; Thomas
Jr., Mullis and Johnson, 1994). In view of this, one
million HIY-positive but healthy Americans, and 17
million HIV-positive but healthy humans on this plan-
et (Merson, 1993; National Institute of Allergy and
Infectious Disease, 1994; World Health Organization,
1995), are subjected to a multiplicity of psychological
and sociological pressures (Anonymous, 1992; Dues-
berg, 1992; Schmalz, 1992b; Schmalz, 1992a; Miami
Herald, 1994; Yarbo, 1994).
They are given a death sentence by the medical
establishment for being HIV-positive; they are denied
coverage by health insurance companies; they lose
their jobs and social status; they are denied entrance
visas to many countries including the U.S.; they are
denied employment by the US Army; and worst of all
they are pressured to accept the toxic AZT therapy -
all of this, only because they have made antibodies
against a virus that is presumed to cause AIDS. If they
refuse to submit to these pressures, they are charged
with denial (of the HIV-AIDS hypothesis) by the AIDS
establishment (Moss, Osmond & Bacchetti, 1988; San
Francisco Project Inform, 1992).
In sum, the public health record of the HIV-AIDS
hypothesis in America adds up to a staggering deficit:
for $35 billion (Duesberg, 1994b; AIDS Weekly, 1995;
Gutknecht, 1995) there is no cure, no vaccine, no effec-
tive prevention, hundreds of thousands are subjected to
psychological pressures resulting from positive HIV-
tests, and several million American drug addicts are
denied available information that recreational drugs
cause AIDS-defining and other diseases (Drug Strate-
gies, 1995), and about 150000 are subjected annually
to AZT poisoning - many just for being HIY-positive,
not for having AIDS (Duesberg, 1992).
7. The drug-AIDS hypothesis
Given no evidence for infectious AIDS, the reasons
for the original 'lifestyle hypothesis', and the logic
255
of Sherlock Holmes - that 'when you have eliminated
the impossible, whatever remains however improbable
must be the truth' - AIDS must be non-infectious.
In view of this I propose that:
All AIDS diseases in America and Europe that
exceed their long-established, normal backgrounds are
caused by the long-term consumption of recreational
drugs and by AZTand its analogs.
Hemophilia-AIDS, transfusion-AIDS, and the
extremely rare AIDS cases of the general population
reflect the normal incidence ofAZT-induced incidence
of these diseases under a new name.
African AIDS is a new name for an old disease
caused by malnutrition, parasitic infections and poor
sanitation (Duesberg, 1991; Duesberg, 1992, Dues-
berg, 1994a).
Indeed, the recreational drug use epidemics, that
started in America and Europe during the Vietnam war,
are the only new health risk of the Western World
since World War II. Since its beginnings the drug
use and AIDS epidemics in the US and Europe have
coincided both epidemiologically, and chronologically
(Duesberg, 1992). About 33% of all American AIDS
patients, nearly all heterosexuals, are intravenous drug
users (Centers for Disease Control and Prevention,
1994b). Over 60% are male homosexuals who have
used psychoactive and aphrodisiac drugs orally such as
nitrite inhalants, amphetamines, cocaine and phenyl-
cyclidine (Table 2). Many of these recreational drug
users and most of the few AIDS patients who have
not used recreational drugs have used AZT and cyto-
toxic DNA chain terminators as anti-HIV drugs (see
below) (Duesberg, 1992; Duesberg, 1994a). Allowing
a 'latent period of 10 years' for chronic recreational
drug use to cause AIDS, the beginning of the Amer-
ican drug use epidemics in the late 1960s and 1970s
predicts exactly the origin of AIDS in the 1980s.
Unlike the virus-AIDS hypothesis, the drug
hypothesis has a plausible chemical and experimen-
tally testable basis. The recreational drugs postulated
to cause AIDS have strong biochemical and psychoac-
tive effects every time they are taken - the reason for
their popularity. By contrast, HIY is latent, and neither
chemically or clinically detectable in 'HIV antibody-
positives' with and without AIDS. Despite 11 years
of unprecedented research efforts no biochemical evi-
dence has been found in support of the HIV-AIDS
hypothesis (Cohen, 1995).
256

Indirect toxicity is the result of malnutrition and

Table 2. Drug use by homosexuals at risk for AIDS.
insomnia which in turn are consequences of drug-
In 1983 the CDC reported the following drug use of 170 male induced suppression of appetite and fatigue (Layon et
homosexuals, 50 with Kaposi's sarcoma and pneumonia and al., 1984; Lerner, 1989; Pillai, Nair & Watson, 1991;
120 without AIDS (Jaffe et al., 1983): Duesberg, 1992; Larrat & Zierler, 1993; Mientjes et
96% nitrite inhalants al., 1993; Sadownick, 1994). These problems are com-
35-50% ethylchioride inhalants pounded by poverty due to the enormous costs of illicit
50--60% cocaine drugs. Direct, long-term pathogenic effects of cocaine
50-70% amphetamines and heroin have not been studied owing to the general
40% phenylcycJidine disregard of drug toxicity (Duesberg, 1992).
40-60% LSD
40-60% metaqualone (2) Cytotoxic and genotoxic. Nitrite inhalants are cyto-
25% barbiturates
toxic, and thus are immunotoxic in animals and humans
90% marijuana
(Goedert et aI., 1982; Ha~erkos & Doughtery, 1988).
10% heroin
A recreational dose of 1 ml per day (Haverkos &
In 1987 (Darrow et al., 1987) and again in 1990 (Lifson
Dougherty, 1988; Duesberg, 1992) corresponds to
et al., 1990) the CDC reported the following drug use about 15 ppm in a 75 kg-person, and corresponds to
for a group of 359 homosexual men from San Francisco: 107 nitrite molecules for everyone of the 1014 cells
84% cocaine in the human body. The cytotoxicity of nitrites on
82% alkylnitrites the epithelial tissues of the lung are enhanced by the
64% amphetamines toxins of cigarette smoke, which also suppresses the
51 % quaaludes immunesystem (Nieman et aI., 1993).
41 % barbiturates In addition nitrite inhalants are among the
20% injected drugs best established mutagens and carcinogens (National
Research Council, 1982; Lewis, 1989; Winter, 1989;
According to analyses by Duesberg (Duesberg, 1993d); Ellison Mirvish et aI., 1993).
et al. (Ellison, Downey & Duesberg, 1995) and M. Craddock
In view of the toxicity of nitrite inhalants, a pre-
(This volume) nearly all male homosexual AIDS patients in
scription requirement was instated by the US Food and
cohorts from San Francisco (Ascher et al., 1993) and
Drug Administration in 1969 (Newell et al., 1985a),
Vancouver (Schechter et al., 1993b) had used nitrites,
and because of an 'AIDS link' (Cox, 1986) the sale of
cocaine, amphetamines and AIr
HIV- Drug AIDS healthy
nitrites was banned by the U.S. Congress in 1988 (Pub-
positives use
lic Law 100-690) (Haverkos, 1990) and by the 'Crime
Control Act of 1990' (Duesberg, 1992). Moreover, the
San Francisco 445 100% 215 230 US Food and Drug Administration limits nitrites as
Vancouver 365 >98% 136 229 food preservatives to less than 220 ppm, because of
direct toxicity and because 'they have been implicated
in an increased incidence of cancer' (Lewis, 1989).

The specific toxicity and dosages of recreational
and medical drugs used by American and European
AIDS risk groups can explain all AIDS diseases (Dues-
berg, 1992). AIDS drugs are either indirectly toxic, or
cytotoxic, or genotoxic and cytotoxic.
(1) Indirectly toxic. Cocaine, amphetamines and hero-
in are indirectly immunotoxic. All three function as
catalysts in the human body. Cocaine and heroin are
natural compounds and amphetamines are synthetic
adrenalins first developed in Germany during World
War II to suppress fatigue and anxiety in pilots and
tank commanders (Weil & Rosen, 1983).
(3) Genotoxic-cytotoxic. AZT, ddI and other DNA
chain terminators are directly toxic by killing all grow-
ing cells, in particular the fastest growing ones -
the hematopoietic and epithelial cells (Fig. 2), (Mer-
ck Research Laboratories, 1992; Chiu & Duesberg,
1995). In addition, AZT prevents mitochondrial DNA
synthesis in non-growing cells, such as neurons or
muscles, and can be carcinogenic by mutating cells
(Duesberg, 1992; Parker & Cheng, 1994; Pluda et al.
1990).
The key to the drug hypothesis is that only long-
term consumption causes irreversible AIDS-defining
diseases. Occasional or short-term recreational drug

use causes reversible diseases or no disease at all. With
drugs, the dose is the poison. Yet, most studies inves-
tigating the effects of recreational drugs are concerned
with their short-term psychoactive rather than their
10ng-termc1inical effects (Duesberg, 1992). For exam-
ple, it takes 20 years of smoking to acquire irreversible
lung cancer or emphysema, and 20 years of drinking
to acquire irreversible liver cirrhosis. In contrast to
drugs, infectious agents are self-replicating toxins. By
multiplying exponentially in the body infectious agents
generate sufficient doses of toxic substances to cause
diseases within days or weeks.
Since currently no experiments are done in Amer-
ica, to test the drug hypothesis, I have evaluated the
drug-AIDS hypothesis on the basis of its predictions. In
contrast to the HIV-AIDS hypothesis, the drug hypoth-
esis can predict all parameters of American/European
AIDS.
9. The drug-hypothesis predicts the
American/European AIDS
epidemic-completely
9.1 AIDS is restricted to intravenous and oral users of
recreational drugs and of AZT, because drugs cause
AIDS
Since 1981 94% of all American AIDS cases have
been from risk groups who had used such drugs (Cen-
ters for Disease Control and Prevention, 1994c). About
one-third of these were intravenous drug users (Cen-
ters for Disease Control, 1993) and two-thirds were
male homosexuals (Centers for Disease Control and
Prevention, 1994c; Centers for Disease Control and
Prevention, 1994a) who had used oral recreational
drugs and AZT (Duesberg, 1992; Ascher et al., 1993;
Duesberg, 1993c; Duesberg, 1993a; Duesberg, 1993d;
Parke, 1993; Schechter et al., 1993b). HIV-positive
hemophiliacs and transfusion recipients also receive
AZT as an antiviral drug (Duesberg, 1992; Duesberg,
1995b). (However, a small percentage of hemophiliacs
annually develop a specific subset of AIDS-defining
immunodeficiency diseases, mostly pneumonia and
candidiasis, only from the long-term transfusion of
foreign proteins that contaminate commercial factors
VIII (Duesberg, 1992; Duesberg, 1995b).) European
AIDS also correlates with drug consumption (Dues-
berg, 1992).
257
9.2 American/European AIDS predominantly affects
adult males, because they are the predominant users
of recreational drugs and AZT
The CDC reports that 87% of all American AIDS
patients are males (Centers for Disease Control and
Prevention, 1994c). This number is the sum of the fol-
lowing constituents: The National Institute on Drug
Abuse and the Bureau of Justice Statistics report that
over 75% of hard, recreational drugs are consumed
intravenously by males (Duesberg, 1992). According
to the federally supported Drug Strategies program,
'women account for the fastest-growing populations in
jails and prisons, in large part because of drug offenses'
(Drug Strategies, 1995). Therefore the CDC reports
that women are now the fastest growing AIDS risk
group (Centers for Disease Control, 1994; Centers for
Disease Control and Prevention, 1994a).
The CDC and independent investigators also report
that nearly all male homosexuals with AIDS and
at risk for AIDS are long-term users of oral drugs
such as nitrite inhalants, ethylchloride inhalants,
amphetamines, cocaine, and others to facilitate sex-
ual contacts, particularly anal intercourse (Lifson et
al., 1990; Duesberg, 1992; Ascher et al., 1993; Dues-
berg, 1993d; Schechter et al., 1993a; Schechter et al.,
1993c). The drug use of male homosexuals with AIDS
or at risk for AIDS reported by the CDC (Jaffe et al.,
1983; Darrow et al., 1987; Lifson et al., 1990) and oth-
ers (Ascher et al., 1993; Duesberg, 1993d; Schechter
et al., 1993c; Ellison, Downey & Duesberg, 1995)
as of 1983 is listed in Table 2. Ostrow reported that
nitrite use in a cohort of over 5000 male homosexu-
als from Chicago, Baltimore, Los Angeles and Pitts-
burgh showed a 'consistent and strong cross-sectional
association with ... anal sex' (Ostrow, 1994). In addi-
tion, many HIV-positive homosexuals are prescribed
AZT as an antiviral drug (Duesberg, 1992; Duesberg,
1993d).
Since intravenous drug users, who are 75% male,
make up one third of all AIDS patients, and male homo-
sexuals make up almost two-thirds of all American
AIDS patients, the drug hypothesis explains why 87%
of all American AIDS patients are males.
9.3 Pediatric AIDS occurs because of maternal drug
addiction
Indeed about 80% of pediatric AIDS cases in America
and Europe are children born to mothers who were
intravenous drug users during pregnancy (see below
(5) and (8)), (Mok et al., 1987; European Collaborative
258
Study, 1991; Duesberg, 1992). The remainder reflects
the normal incidence of AIDS-defining diseases among
newborns.
9.4 American AIDS is new and increasing steadily,
because the American drug epidemic is new and
increasing steadily
In the u.S. recreational drug use is epidemiologically
new, as it has increased over the last decades from
statistically undetectable levels to epidemic levels at
about the same rate as AIDS (Duesberg, 1992).
For example, cocaine consumption increased 200-
fold from 1980 to 1990, based on cocaine seizures
that increased from 500 kg in 1980 to 100000 kg in
1990 (Duesberg, 1992). During the same time cocaine-
related hospital emergencies increased from 3,296 cas-
es in 1981, to 80,355 cases in 1990, to 199,843 in 1992
and to over 120,000 in 1993 (Duesberg, 1992; Meddis,
1994; Drug Strategies, 1995) (Fig. 1B).
In the last three years, the increase of cocaine con-
sumption has slowed down at the expense of increas-
es in heroin consumption, which were accompanied
by increases in heroin-related hospital emergencies
(Gettman, 1994; Meddis, 1994). Heroin-related hos-
pital emergencies doubled, from over 30 000 in 1990
to over 60 000 in 1993 (Drug Strategies, 1995 (Fig.
lB».
Amphetamine consumption has increased 100-fold
from 1980 to 1990 (Bureau ofJustice Statistics, 1991).
Non-scientific reports describe new upsurges in the
consumption of amphetamines (Sadownick, 1994) and
the 'gay drug' (nitrite inhalants) (Mirken, 1995) among
male homosexuals. According to a recent report from
the National Institute on Drug Abuse and the CDC,
'nitrite use has increased in the 1990s in gay men in
Chicago and San Francisco' after a decline in the 1980s
(Haverkos & Drotman, 1995).
Drug offenders are now the 'largest and fastest-
growing category in the Federal prisons population,
accounting for 61 % of the total, compared with 38% in
1986'. The number of Federal drug offenders increased
from about SOC:> in 1980 to about 55000 in 1993. In
1993, between 60 and 80% of the 12 million prisoners
in the US had been on illicit drugs (Drug Strategies,
1995).
The German Rauschgiftbilanz, reports an 11.2%
increase in the consumption of illici t recreational drugs
in 1994 compared to 1993 (Rauschgiftbilanz 1994,
1995).
Consider a grace period of about 10 years to achieve
the dosage needed to cause irreversible disease, and
you can date the origin of AIDS in 1981 as a conse-
quence of the drug use epidemic that started in Amer-
ica in the late 1960s during the Vietnam War. Indeed,
AIDS increased from a few dozen cases annually in
1981 to about 100000 in 1993 (Fig. 1A) (Centers for
Disease Control and Prevention, 1994c). Note the par-
allelisms between the spread of AIDS and the spread
of cocaine and cocaine-related hospital emergencies
since 1981 (Fig. 1), and the contrast with the non-
spread of HIV, the hypothetical cause of AIDS, since
1984 (Fig. 1A). Thus both, the newness and the spread
of the AIDS epidemic, are predictable by the drug-
AIDS hypothesis.
The growth of the epidemic has been accelerated
by AZT. Since its introduction in 1987, AZT is now
prescribed to about 200 000 HIV-positives worldwide
(Duesberg, 1992; Thomas, 1995).
9.5 Only a small fraction of drug users develop AIDS,
because only the highest cumulative drug doses cause
irreversible diseases
The cumulative total of 401 ,749 American AIDS cases
since 1981 that were reported in June 1994 (Centers
for Disease Control and Prevention, 1994c) have been
recruited from a much larger reservoir of drug users.
There are currently between 3 (Drug Strategies, 1995)
and 8 million cocaine addicts (Duesberg, 1992) and
0.6 million heroin addicts in the US (Drug Strategies,
1995). In 1980, 5 million Americans had used nitrite
inhalants. In 1989, 100 million doses of amphetamines
were consumed in the U.S. (Duesberg, 1992).
According to the 1994-survey of the National Insti-
tute on Drug Abuse, 'more than 5 percent (221 000) of
the 4 million women who give birth each year use illic-
it drugs during pregnancy.' (Drug Strategies, 1995).
These mothers are the reservoir from which most of
the 10 17 pediatric AIDS cases reported in the US in
1994 were recruited (Centers for Disease Control and
Prevention, 1994b) (see below).
Unfortunately, scientific documentation of recre-
ational drug use is extremely sporadic and inaccessi-
ble, not only because these drugs are illegal, but more
importantly because the medical-scientific community
is totally uninterested in drugs as a cause of AIDS (see
10).
In addition, about 150 000 HIV-positive Ameri-
cans were on AZT between 1992 and 1995 (Duesberg,
1992; Thomas, 1995). Probably because drug toxicity

is generally ignored, there are also no national statis-
tics available on how many HIV-positive Americans
are on AZT and other anti-HIV drugs, that, like AZT,
are designed to kill human cells (Duesberg, 1992).
The small percentage of AIDS patients among the
many American drug users reflects the highest lifetime
dose of drug use, just like the lung cancer and emphy-
sema patients reflect the highest lifetime tobacco dose
among the 50 million smokers in the U.S. The long
'latent period of HIV' is a euphemism for the time
needed to accumulate the drug dosage that is sufficient
for AIDS. Indeed it takes about 10 years of injecting
heroin and cocaine to develop weight loss, tubercu-
losis, bronchitis, pneumonia and other drug-induced
diseases (Layon et al., 1984; Schuster, 1984; Savona
et al., 1985; Donahoe et ai., 1987; Espinoza et al.,
1987; Weber et al., 1990).
The time lag from initiating a habit of inhaling
nitrites to acquire Kaposi's sarcoma has been deter-
mined to be 7 to 10 years (Newell et al., 1985a; Beral
et al., 1990; Lifson et al., 1990; Duesberg, 1992).
Blaming Kaposi's sarcoma after inhaling carcinogenic
nitrites for 10 years on HIV is like blaming lung cancer
and emphysema after smoking two packs of cigarettes
a day on a virus that would cause these diseases after
latent periods of 10 to 20 years. ~ tinction between classic and AIDS Kaposi's sarco-
AZT, at the currently prescribed high doses of 0.5 to
1.5 grams per person per day, causes many of the above
described AZT-specific diseases faster than recreation-
al drugs, i.e. within weeks or months after administra-
tion (Duesberg, 1992; Lewis-Thorton, 1994).
9.6 Risk group-specific AIDS diseases occur because
of risk group-specific drugs
Group-specific drug use explains the following risk
group-specific AIDS diseases:
(i) Kaposi's sarcoma specific for male homosexuals.
Kaposi's sarcoma as an AIDS diagnosis is 20-times
more common among homosexuals who use nitrite
inhalants than among AIDS patients who are intra-
venous drug users, or hemophiliacs (Haverkos &
Dougherty, 1988; Beral et al., 1990). Due to the
carcinogenic potential, nitrites were originally pro-
posed as causes of Kaposi's sarcoma (Marmor et
ai., 1982; Haverkos et al., 1985). 'Aggressive and
life-threatening' Kaposi's sarcoma, particularly pul-
monary Kaposi's sarcoma, is exclusively observed in
male homosexuals (Sloand, Kumar & Pierce, 1993;
Meduri et ai., 1986; Garay et al., 1987; Gill et al.,
1989). Since the lungs are the primary site of expo-
259
sure to nitrite inhalants the evidence, that up to 32% of
Kaposi's sarcomas of homosexual men can be diag-
nosed as pulmonary Kaposi's sarcoma (Gill et al.,
1989; Irwin & Kaplan, 1993), lends additional support
to the nitrite-Kaposi's sarcoma hypothesis. Pulmonary
Kaposi's sarcoma has never been observed by Moritz
Kaposi (Kaposi, 1872) nor by others prior to the AIDS
epidemic.
It appears that the nitrite-induced AIDS Kaposi's
sarcoma and the classic Kaposi's sarcomas are entire-
ly different cancers under the same name. The 'HIV-
associated' Kaposi's sarcomas observed in male homo-
sexuals are 'aggressive and life-threatening' (Sloand,
Kumar & Pierce, 1993), fatal within 8-10 months after
diagnosis, and often located in the lung (Meduri et
al., 1986; Garay et al., 1987; Gill et al., 1989; Irwin
& Kaplan, 1993). The classic 'indolent and chron-
ic' Kaposi's sarcomas are diagnosed on the skin of
the lower extremities and hardly progress over many
years (Meduri et al., 1986; Drotman & Haverkos,
1992; Cohen, 1994a). Meduri et al. point out that 'pul-
monary involvement by the neoplasma has been an
unusual clinical finding' in the Kaposi's sarcomas of
male homosexuals compared to all 'classic' Kaposi's
sarcomas (Meduri et al., 1986). Nevertheless, the dis-
ma is hardly ever emphasized and may have escaped
many observers due to the 'difficulty in pre-mortem
diagnosis', because 'pulmonary Kaposi's sarcoma was
indistinguishable from opportunistic pneumonia ... '
(Garay et al., 1987).
The immunotoxicity and cytotoxicity of nitrites
explains the proclivity of male homosexual nitrite users
for pneumonia, which is the most common AIDS dis-
ease in the U.S. and Europe (Haverkos & Dougher-
ty, 1988; Duesberg, 1992) (Table 1). Moreover
the immunotoxins and cytotoxins of cigarette smoke
explain, why in two groups of otherwise matched HIV-
positive male homosexuals cigarette smokers devel-
oped pneumonia twice as often as non-smokers over a
period of 9 months (Neiman et al., 1993.
(ii) High mortality of intravenous drug users. Intra-
venous drug users suffer from long-term malnutrition
and insomnia, which are primary causes of immun-
odeficiency worldwide (Seligmann et al., 1984). This
explains the tuberculosis, pneumonia, and weight loss
that are typical of these risk groups (Layon et al., 1984;
Stoneburner et al., 1988; Pillai, Nair & Watson, 1991;
Duesberg, 1992; Mientjes et al., 1993). Injection of
unsterile drugs combined with immunodeficieny also
cause septicemia and endocarditis that are common in
260
AIDS patients who are intravenous drug users (Dues-
berg, 1992). As a result intravenous drug users die at a
very low average age. A German study found mY-free
intravenous drug users to die at 29.6 years and my-
positive intravenous drug users at 31.5 years (Locke-
mann et at., 1995) and an American study showed that
both mY-positive and mY-negative intravenous drug
users develop the same diseases (Stoneburner et aI.,
1988).
(iii) Low birth weight and mental retardation ofAIDS
babies. 80% of American/European babies with AIDS
are born to mothers who were intravenous drug users
during pregnancy. They acquire low birth weight, men-
tal retardation and immunodeficiency through maternal
drug use (Duesberg, 1992; Drug Strategies, 1995). The
B-cell deficiencies, and certain bacterial infections that
are both only considered AIDS-defining in children
are also specific expressions of their acquired immuno-
deficiency (Centers for Disease Control, 1987; Centers
for Disease Control and Prevention, 1992; Duesberg,
1992).
(iv) Anemia, wasting and high mortality ofAZT recip-
ients. Anemia, leukopenia, pancytopenia, diarrhea,
weight loss, hair loss, impotence (Duesberg, 1992),
hepatitis (Freiman et at., 1993) and pneumocystis
pneumonia (Saah et al., 1995) that are observed in
recipients of AZT and other DNA chain terminators,
are predictable consequences of the cytotoxicity of
these drugs. In addition, non-renewal of mitrochondri-
al DNA causes muscle atrophy, hepatitis, and demen-
tia; and carcinogenic activity causes cancer such as
lymphoma in AZT recipients (Pluda et aI., 1990; Dues-
berg, 1992; McLeod & Hammer, 1992; Freiman et
aI., 1993; Bacellar et al., 1994; Parker & Cheng,
1994; Physicians'Desk Reference, 1994). Compared
to untreated controls AZT recipients die 2A-times
more often (Goedert et al., 1994), 25% more often
(Seligmann et aI., 1994), or live only 2 years instead
of 3 years with AIDS (Poznansky et aI., 1995).
9.7 Non-correlation between HN and AIDS, because
drugs, not HN, cause AIDS
(i) Long-term survivors or 'non-progressors'. Per-
sons infected by my for more than the 10-year-
latent-period-from-mY-to-AIDS who are studied by
mv researchers are termed long-term survivors and
more recently 'non-progressors' (Scolaro, Durham &
Pieczenik, 1991; Learmont et al., 1992; Cao et al.,
1995). David Ho et al. recently gave a key to long-
term survival, 'none had received antiretroviral thera-
py' (Cao et al., 1995). Likewise Alvaro Munoz report-
ed that not one of the long-term survivors of the largest
federally funded study of male homosexuals at risk
for AIDS, the MACS study, had used AZT (Munoz,
1995). And several survey studies documented that in
addition to abstaining from antiviral drugs long-term
survivors are those who have given up or never taken
recreational drugs (Wells, 1993; Gavzer, 1995; Root-
Bernstein, 1995b).
Indeed, the vast majority of mY-positives are long-
term survivors. Worldwide, they number 17 million,
including 1 million mY-positive but healthy Ameri-
cans and 0.5 million mY-positive but healthy Euro-
peans (Merson, 1993; World Health Organization,
1995). Most of these have been mY-positive for at least
10 years now, because their numbers have not changed
since the time between 1984 and 1988, when the epi-
demic of mY-testing began (Duesberg, 1992).
Only about 6% (or 1,025,073) of these 17 million
mY-positives have developed AIDS diseases since
AIDS statistics are kept (World Health Organization,
1995). Since no more than 6% of mY-carriers world-
wide have developed AIDS in 7 to 10 years, the annual
AIDS risk of an mY-carrier is less than 1% per year.
However, even this low figure is not corrected for the
normal occurence of the 29 AIDS-defining diseases
in mY-free controls. There is no evidence that mv-
positive people who are not drug users have a higher
morbidity or mortality than mY-free controls (Dues-
berg, 1995a).
(ii) Intravenous drug users and male homosexuals los-
ing their T-cells prior to HN infection. Prospective
studies of male homosexuals using psychoactive and
sexual stimulants have demonstrated that their T-cells
may decline prior to infection with my. For exam-
ple, the T-cells of 37 homosexual men from San Fran-
cisco declined steadily prior to my infection for 1.5
years from over 1200 to below 800 per J.tl (Lang et
al., 1989). In fact, some had fewer than 500 T-cells
1.5 years before seroconversion (Lang et al., 1987).
Although recreational drug use was not mentioned in
these articles, other studies of the same cohort of homo-
sexual men from San Francisco described extensive
use of recreational drugs including nitrites (Darrow et
al., 1987; Moss, 1987; Ascher et al., 1993; Dues-
berg, 1993d; Ellison, Downey & Duesberg, 1995).
Likewise 33 mY-free male homosexuals from Van-
couver, Canada, had' acquired' immunodeficiency pri-
or to my infection (Marion et al., 1989). Again this
study did not mention drug use, but in other articles the
authors reported that all men of this cohort had used

nitrites, cocaine and amphetamines (Archibald et at.,
1992; Duesberg, 1993f; Schechter et at., 1993c).
The largest study of this kind reported that about
450 (16% of 2795) HIV-free, homosexual American
men of the MACS cohort from Chicago, Baltimore,
Pittsburgh and Los Angeles had acquired immunodefi-
ciency, having less than 600 T-cells per pI, prior to HIV
infection (Kaslow et at., 1989). Many HIV-positive
and negative men of this cohort had essentially the
same degree of lymphadenopathy: 'Although seropos-
itive men had a significantly higher mean number of
involved lymphnode groups than seronegative men
(5.7 compared to 4.5 nodes, p < 0.005), the numer-
ical difference in the means is not striking' (Kaslow
et at., 1987). According to previous studies on this
cohort 71 % of these men had used nitrite inhalants, in
addition to other drugs (Kaslow et at., 1987); 83% had
used one drug, and 60% had used two or more drugs
during sex in the previous six months (Ostrow et at.,
1990).
Another study of the same cohort reports that the
risk of developing AIDS prior to and after HIV infec-
tion correlated with the frequency of receptive anal
intercourse, rather than with HIV (Phair et at., 1992).
Other investigations have shown that receptive anal
intercourse correlates directly with the use of nitrite
vasodilaters (Haverkos & Dougherty, 1988; Duesberg,
1992; Parke, 1993).
Thus in male homosexuals at risk for AIDS a
decrease in T-cells often precedes infection by HIV,
not vice versa. Since the cause must precede the con-
sequence, drug use remains the only choice to explain
'acquired' immunodeficiencies prior to HIY. If male
homosexuality were to cause immunodeficiency, about
10% of the adult American male population should
have AIDS (Duesberg, 1992; Seidmann & Rieder,
1994).
Prospective studies of intravenous drug users also
document T-cell losses prior to infection by HIY. For
example, among intravenous drug users in New York
'the relative risk for seroconversion among subjects
with one or more CD4 [T-cell] counts <500 cells/pi
compared with HIV-negative subjects with all counts
>500 cells/pI was 4.53' (Des Jarlais et at., 1993). A
similar study from Italy showed that a low number of
T-cells was the highest risk factor for HIV infection
(Nicolosi et at., 1990). Again, a decrease in T-cells is
a risk factor for HIV infection, and not vice versa.
This confirms the hypothesis that HIV is a marker
of drug consumption, rather than the cause of AIDS
(see 4): the more drugs are consumed intravenously or
261
for sex, the higher is the risk of HIV infection (Dues-
berg, 1992).
(iii) HIV-free AIDS. One summary of the AIDS liter-
ature describes over 4,621 clinically diagnosed AIDS
cases who were not infected by HIV (Duesberg, 1993f).
Additional cases are described that were not in this
summary (Kaslow et al., 1987; Lang et al., 1987;
European Collaborative Study, 1991; Weiss et al.,
1992; Ellison, Downey & Duesberg, 1995; Moore
& Chang, 1995). They include intravenous drug users,
male homosexuals using aphrodisiac drugs like nitrite
inhalants, and hemophiliacs developing immune sup-
pression from long-term transfusion offoreign proteins
contaminating factor VIII (Duesberg, 1993f; Dues-
berg, 1995b).
Each of these non-correlations between HIV and
AIDS are predicted by the hypothesis that recreation-
al drugs and other non-contagious risk factors cause
AIDS.
9.8 Discontinuation of drug use either stabilizes or
cures AIDS and other diseases - even in
HIV-positives
(i) AZT. Ten out of 11 HIV-positive, AZT-treated AIDS
patients recovered cellular immunity after discontinu-
ing AZT in favour of an experimental vaccine (Scolaro,
Durham Pieczenik, 1991). Two weeks are discontin-
uing AZT, 4 out of 5 AIDS patients recovered from
myopathy (Till & MacDonnell, 1990). Three of four
AIDS patients recovered from severe pancytopenia and
bone marrow aplasia 4-5 weeks after AZT was discon-
tinued (Gill et at., 1987).
(ii) Heroin/cocaine. The incidence of AIDS diseases
among HIV-positive intravenous drug users over 16
months was 19% (23/124) and only 5% (5/93) among
those who stopped injecting drugs (Weber et aI., 1990).
The T-cell counts of HIV-positive intravenous drug
users from New York dropped 35% over 9 months,
compared to HIV-positive controls who had stopped
injecting (Des Jarlais et al., 1987).
(iii) Recreational drugs and AZT. The health of male
homosexuals is stabilized or even improved by avoid-
ing recreational drugs. For example in August 1993
there was no mortality during 1.25 years in a group of
918 British HIV-positivehomosexuals who had 'avoid-
ed the experimental medications on offer' and chose
to 'abstain from or significantly reduce their use of
recreational drugs, including alcohol' (Wells, 1993).
Assuming an average 10-year latent period from HIV
to AIDS, the virus-AIDS hypothesis would have pre-
262
dicted at least 58 (918/10 x 1.25 x 50%) AIDS cases
among 918 HIV-positives over 1.25 years. Indeed, the
absence of mortality in this group over 1.25 years cor-
responds to a minimal latent period from HIV to AIDS
of over 1,148 (918 x 1.25) years. On July 1, 1994
there was still not a single AIDS case in this group
of 918 HIV-positive homosexuals (J. Wells, London,
personal communication).
The T-cells of 29% of 1,020 HIV-positive male
homosexuals and intravenous drug users in a clinical
trial even increased over 2 years (Hughes et al., 1994).
These HIV-positives belonged to the placebo arm of
an AZT trial for AIDS prevention and thus were not
intoxicated by AZT. It is probable that under clinical
surveillance the 29% whose T-cells increased despite,
HIV, have given up or reduced immunosuppressive
recreational drug use in the hope that AZT would work.
(iv) AIDS babies, born to drug-addicted mothers,
recover after birth. HIV-positive babies, born to moth-
ers who were intravenous drug users during pregnancy,
provide some of the best examples for the prediction
that termination of drug use prevents, or cures AIDS-
despite the presence of HIV For example, Blanche et
al. have observed for three years 71 HIV-positive new-
borns who have shared intravenous drugs with their
mothers prior to birth. Ten of these children developed
encephalopathy and AIDS-defining diseases of which
9 died during their first 18 months of life. The study
points out that the risk of a newborn to develop AIDS
was related 'directly with the severity of the disease in
the mother at the time of delivery' and that based on the
severity of their symptoms children were also treated
prophylactically with AZT and sulfa drugs (Blanche et
al., 1994).
Despite HIV, 61 of the 71 HIV-positive children
either developed only 'intermittent' diseases from
which they recovered during their first 18 months or
developed no disease at all during the 3 years of obser-
vation. The T-cells of these children increased after
birth from low to normal levels - despite the presence
ofHIV
A very similar picture emerges from a collaborati ve
European study of HIV-positi ve newborns (The Euro-
pean Collaborative Study, 1994). The study reports
that about 20% of the HIV-positive children had died
or developed long-term AIDS during the first year after
birth, and another 20% during the second and third
year. About 10% of the children were 'treated with
zidovudine [AZT], before 6 months of age and 40% by
4 years (The European Collaborative Study, 1994).
Over 60% of congenitally-infected children proved
to be healthy up to 6 years after birth - despite the pres-
ence of HIV Most of these had experienced transient
AIDS diseases, such as pneumonia, bacterial infec-
tions, candidiasis and cryptosporidial infection during
the first year after birth.
Although this study does not even mention the
health and health risks of the mothers, previous reports
from the European Collaborative Study group have
documented that 'nearly all children were born to
mothers who are intravenous drug users' (Mok et al.,
1987; Duesberg, 1992). In 1991, the European Collab-
orative Study group reported that 80% of the children
with pediatric AIDS were born to mothers who were
intravenous drug users (European Collaborative Study,
1991). The 1991-study further points out that 'children
with drug withdrawal symptoms' were most likely to
develop diseases, and that children with no withdraw-
al symptoms but 'whose mothers had used recreational
drugs in the final 6 months of pregnancy were inter-
mediate' in their risk to develop diseases (European
Collaborative Study, 1991).
According to the HIV hypothesis every infected
baby should have developed AIDS and progressive-
ly lost T-cells, and according to HIV plus cofactor
hypothesis, at least all those with intermittent dis-
eases should have progressed to AIDS. This was not
observed.
According to the drug hypothesis, the AIDS risk
of the children is a function of the drugs consumed.
Those who received the highest doses of drugs before
birth would have acquired irreversible diseases and
those who acquired diseases from sublethal thresholds
would be able to recover after cessation of maternal-
ly administered drugs. Indeed, both, the European
Collaborative Study group and Blanche et al. show
that the majority of children gained T-cells and recov-
ered from transient diseases after discontinuation of
maternal drug input-despite the presence of HIV The
childrens risk for AIDS was related 'directly with the
severity of the disease in the mother' (Blanche et al.,
1994), which is an expression for the extent of drug
consumption by the mother.
Moreover, the harm of maternal drug consumption
to sick babies was compounded after birth, because
'prophylatic treatment [with] ... sulfamethoxazale and
zidovudine [AZT] was started earlier and was more
frequent among the 16 children born to mothers with
class IV disease (AIDS), (Blanche et al., 1994). (The
Blanche study did include mothers with AIDS who
were not intravenous drug users). The European Col-

laborative Study group reports that 10 to 40% of HIV-
positive children were treated with AZT.
It follows that discontinuation of recreational and
antiviral drug use stabilizes, even cures AIDS in HIV-
positive persons.
Likewise the T-cells of HIV-positive hemophili-
acs increase after removal of immunosuppressive for-
eign proteins from their factor VIII therapy (Dues berg,
1995), and the T-cells of African HIV-positive tuber-
culosis patients increase after 'standard anti-TB treat-
ment' and improved nutrition (Martin et at., 1995).
In sum, the drug-AIDS hypothesis correctly pre-
dicts all aspects of AmericanlEuropean AIDS, while
the HIV-hypothesis predicts none.
10. A possible solution at last
Testing the drug hypothesis should have a very high
priority in AIDS research, because this hypothesis
makes verifiable predictions (Cohen, 1994a; DeNoon,
1995). Drug toxicity could be tested experimentally in
animals, and in human cells in tissue culture. In addi-
tion, drug toxicity could be tested epidemiologically
in humans who are addicted to recreational drugs or
are prescribed AZT. Such tests could be conducted at
a fraction of the cost that is now invested in the HIV
hypothesis.
If the drug hypothesis proved to be correct, AIDS
would be an entirely preventable disease. Here is
how:
(1) AZT use would be banned immediately.
(2) AIDS from illicit recreational drugs would be
reduced or prevented by education against drug
use. (Hemophilia AIDS would be prevented by the
use of pure factor VIII).
(3) AIDS therapy would be achieved by termination
of recreational drug use and treating AIDS dis-
eases for their specific causes, e.g. tuberculosis
with antibiotics, Kaposi's sarcoma with conven-
tional cancer therapy, and weight loss with good
nutrition - rather than treating each of these unre-
lated diseases with the same cell-killer AZT.
In addition to saving about 100000 lives per year
from AIDS, the drug hypothesis could save the Amer-
ican tax payer up to $20 billion annually. Currently the
federal government spends annually $7.5 billion on
AIDS treatment, research and education (AIDS Week-
ly, 1995; Gutknecht, 1995). And the Federal drug bud-
get currently costs $13 billion, mainly for supply con-
263
trol, interdiction, methadone treatment and 'education'
(Drug Strategies, 1995).
But neither AIDS education nor drug education
ever target the health effects of long-term drug use.
They focus on the legal and social consequences of
drug use and on the effects of drug use on transmission
of HIV via unsafe sex and without 'clean needles'.
Instead of studying the unknown, and warning against
the known health hazards of recreational drugs, the
medical establishment turns a blind eye to drug toxicity
in its single-minded pursuit of HIV with safe sex and
clean needles (Project Inform, 1992; Ascher et at.,
1993; Cohen, 1994a). The clean-needle program ofthe
AIDS-establishment would appear to encourage rather
than discourage intravenous drug use. Reflecting this
state of mind, Science recently rejected the drug-AIDS
hypothesis, quoting a drug researcher that 'Heroin is a
blessedly untoxic drug' (Cohen, 1994a) and described
nitrite inhalant-AIDS links as another 'hatched' theory
(Cohen, 1994b).
The failure to warn against the health risks of drug
addiction is certainly one of the reasons that 'drug
use among young people has risen substantially for
the first time in more than a decade' (Drug Strategies,
1995). Nitrite use continues to remain popular and
has even increased recently, particularly among male
homosexuals (Ascher et at., 1993; Duesberg, 1993d;
Mansfield & Owen, 1993; Parke, 1993; Schechter et
at., 1993b; Schechter et ai., 1993c; Bethell, 1994;
Gorman, 1994; Hodgkinson, 1994; Lauritsen, 1994;
Sadownick, 1994; Vollbrechtshausen, 1994; Brandley,
1995; Haverkos & Drotman, 1995; Mirken, 1995).
There is no report that nitrite bans are ever enforced
or that nitrite warnings are taken seriously (Bethell,
1994; Mirken, 1995). And the number of intravenous
drug-AIDS patients has increased steadily for years in
America (Centers for Disease Control and Prevention,
1994b; Drug Strategies, 1995) - probably because drug
control in America is 'primarily focused on supply
control efforts' (Drug Strategies, 1995).
However, if AIDS and drug education were based
on the health consequences of long-term drug use, it
would be as successful as the federal anti-smoking
program. Based on education that smoking causes lung
cancer, emphysema and heart disease, smoking has
dropped in the US from 42% ofthe adult population in
1965 to 25% in 1995 (Associated Press, 1995b).
The solution of AIDS could be as close as a very
testable, very affordable, and very practicable alterna-
tive hypothesis.
264
Acknowledgements
I thank Ruhong Li for searching the AIDS literature and
assistance with computer programs, Prof. Phil John-
son, School of Law UC Berkeley, for many references
and critical commentary, Russell Schoch for critical
review of the manuscript, Siggi Sachs for preparation
of, and help with the manuscript and Claus Koehnlein
(Kiel Germany) and Colman Jones (Toronto, Canada)
for critical information. This investigation was sup-
ported in part by the Council for Tobacco Research,
USA, and private donations from Thomas Boulger
(Redondo Beach, Calif., USA), Glenn Braswell (Los
Angeles, Calif., USA), Dr. Richard Fischer (Annan-
dale, Va., USA), Dr. Peter Paschen (Hamburg, Ger-
many), Ruth Sackman, president of the Foundation
for the Advancement in Cancer Therapy (New York,
USA).
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1992. Idiopathic CD4+ T-lymphocytopenia. Lancet 340: 608-
609.
Wells, J., 1993. We have to question the so-called 'facts'. Capital
Gay, August 20th, p 14-15.
Winter, R, 1989. A consumer's dictionary of food additives. Crown
Publishers, Inc. New York, NY 10022.
World Health Organization, 1995. The current Global Situation of
the HIV/AIDS Pandemic. Geneva, Jan.
Wyatt, E.A., 1994. Rushing to Judgement. Barron's, August, 15,
p23-27.
Yarbo, S., 1994. Verdict in case of false HIV diagnosis yields more
clients. The Daily Business Review, Nov. 18, p A14.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 271-295, 1996.
© 1996 Kluwer Academic Publishers.
HIV and AIDS: Have we been misled?
Questions of scientific and journalistic responsibility·
Serge Lang
Yale University, New Haven, CT, USA
For a decade, there has been increasing concern about
'AIDS' and a virus called 'HIV' which is said to cause
'AIDS'. Having named this virus 'HIV' - Human
Immunodeficiency Virus - contributes to making peo-
ple accept that 'HIV is the cause of AIDS'. Howev-
er, to an extent which undermines classical standards
of science, some purported scientific results concern-
ing 'HIV' and 'AIDS' have been handled by press
releases, by disinformation, by low quality studies,
and by some suppression of information, manipulating
the media and people at large. I am not here concerned
with intent, but with scientific standards, especially the
ability to tell the difference between a fact, an opinion,
a hypothesis, and a hole in the ground. As we shall
see shortly, there does not even exist a single proper
definition of 'AIDS' on which discourse can reliably
be based. One difficulty of which most people are not
aware, lies in faulty terminology and different impres-
sions by different people of what' AIDS' means. Thus
a morass about HIV and AIDS has been created. I find
it difficult to write systematically about this morass
without becoming part of the morass.
A number of scientists have questioned the estab-
lished view that 'HIV is the cause of AIDS', and they
have given evidence that this view - I call it dogma
- may be invalid. Of course, there are diseases of
which people die. Questions have arisen about which
diseases, under what circumstances, and what causes
them. I shall give examples of the objections which
have been raised about the establishment view, includ-
ing alternative causes for some diseases lumped under
the name 'AIDS'. I shall give examples of the way
alternative hypotheses for the causes of some of these
• Reprinted from the Yale Scientific, fall 1994, updated 5 January
1995.
271
diseases may not have occurred to some researchers,
or have been suppressed.
Raising questions about the view that 'HIV is the
cause of AIDS' , and proposing alternative hypotheses
(e.g. that drug use may be causing certain diseases
under certain circumstances), has sometimes been
interpreted as 'doing a grave disservice to the American
people' or 'having potentially serious adverse public
health consequences'. The scientists who have pro-
posed such alternatives have sometimes been called
'flat earthers'. However, in light of the possibility that
the use of certain drugs and not HIV is causing certain
diseases (e.g. Kaposi's sarcoma), I conclude that not
warning people about this potential danger is doing
them a grave disservice, and may be having serious
adverse public health consequences.
For a decade, billions of dollars have been spent
investigating HIV as a cause of diseases lumped togeth-
er under the name 'AIDS', without success. At the
same time, proposals for funding research on other pos-
sible causes have been rejected. A conclusion summa-
rizing objections to the established view was expressed
by a scientist at a conference of the Pacific Division
of the American Association for the Advancement of
Science in San Francisco on 21 June 1994: 'AIDS will
never be cured until we cure the research.'
I shall also give examples of the way the scientif-
ic community and the public at large are not properly
informed. I shall give examples of how information has
not come from the official scientific press, but from oth-
er sources, e.g. SPIN, the London Sunday Times, the
CalifomiaMonthly (UC Berkeley Alumni Magazine),
and the electronic nets, which sometimes constitute
a contemporary form of samidzat. Thus the scientif-
ic questions which have been raised about the estab-
lished view concerning HIV as 'the cause of AIDS'
set the stage to study how misinformation is spread
272

and accepted uncritically, which is a major issue in its

own right. The mainstream and official scientific press
have promoted the official view about AIDS, most-
ly uncritically. When the official scientific press does
not report correctly, or obstructs views dissenting from
those of the scientific establishment, it loses credibil-
ity and leaves no alternative but to find information
elsewhere.
Thus we find at least two consequences when the
scientific establishment strays from the strict, classical,
scientific standards of evidence, and obstructs dissent
from an official line: some people may not be warned
of practices which may be dangerous to their health,
and the public loses trust in the scientific establishment.

Some important figures
Some scientists who have promoted the establishment
line on AIDS:
Anthony Fauci, Chairman of the National Institute of
Allergy and Infectious Diseases.
Harold Jaffe, Acting Director of the HIV/AIDS divi-
sion of the Center for Disease Control (CDC).
An establishment scientist who has supported AIDS
research on nitrite inhalants:
Harry Haverkos, Clinical director of AIDS research
at the National Institute on Drug Abuse (NIDA).
Some scientists who have raised questions about the
definition and causes of AIDS:
Harvey Bialy, molecular biologist, research editor of
Biotechnology.
Peter Duesberg, Professor of Molecular Biology, UC
Berkeley.
Kary Mullis, Nobel Prize in Chemistry (1993) for
the discovery of the polymerase chain reaction (PCR).
'PCR made it easier to see that certain people are infect-
ed with HIV', as Mullis himself once said.
Robert Root-Bernstein, Associate professor of phys-
iology at Michigan State University, East Lansing;
author of Rethinking AIDS: The Tragic Cost of Pre-
mature Consensus, New York Free Press, 1993; author
of Diversity, Harvard University Press, 1989; former
MacArthur Fellow (1981-1986).
Harry Rubin, Professor of Molecular Biology, UC
Berkeley.
Richard Strohman, Professor Emeritus of Molecular
and Cell Biology, UC Berkeley; former Director of the
Health and Medical Sciences Program at UC Berkeley.
Some journalists:
Celia Farber, author of several articles on AIDS over
several years, in the magazine SPIN.
Neville Hodgkinson, science editor of the London
Sunday Times.
Daniel Koshland, editor of Science.
John Lauritsen, author of The AIDS War and Poison
by Prescription: The AZT Story.
John Maddox, editor of Nature.

WHAT THEY SAID
From and interview (Q&A) with Kary Mullis in the
California Monthly (UC Berkeley Alumni Magazine),
September 1994:
Q: You mentioned Nobel Prize-winner David Balti-
more a moment ago. In a recent issue of Nature, he
said: 'There is no question at all that HIV is the cause
of AIDS. Anyone who gets up publicly and says the
opposite is encouraging people to risk their lives'.
A. So what? I'm not a lifeguard, I'm a scientist. And
I get up and say exactly what I think. I'm not going
to change the facts around because I believe in some-
thing and feel like manipulating somebody's behavior
by stretching what I really know.
I think it's always the right thing and the safe thing
for a scientistto speak one's mind from the facts. If you
can't figure out why you believe something, then you'd
273
better make it clear that you're speaking as a religious
person, not as a scientist. People keep asking me, 'You
mean you don't believe that HIV causes AIDS?' And
I say, 'Whether I believe it or not is irrelevant! I have
no scientific evidence for it'. I might believe in God,
and He could have told me in a dream that HIV causes
AIDS. But I wouldn't stand up in front of scientists
and say, 'I believe HIV causes AIDS because God told
me'. I'd say, 'I have papers here in hand and exper-
iments that have been done that can be demonstrated
to others'. I believe it was decided in the 17th centu-
ry around the founding of the Royal Society that that
was the way science was to stake its claims. It's not
what somebody believes, it's experimental proof that
counts. And those guys don't have that.
The quote by David Baltimore is from the article
'AAAS criticized over AIDS sceptics' meeting', by C.
Maciiwain, Nature 369 (1994) p. 265.
274
1. Gallo-Montagnier and the Gallo-HHS press
conference
The Institut Pasteur discovered the virus called HIY.
Both the Institut Pasteur and Gallo share responsibili-
ty in leading people to believe that 'HIV is the AIDS
virus' , in other words, that AIDS is caused by a virus,
and that this virus is HIY. The controversy between
Gallo and Montagnier of the Institut Pasteur, about
growing the virus and about its use for an HIV-antibody
blood test, was the first major factor in making peo-
ple accept unquestioningly that 'HIV is the virus that
causes AIDS'.
Gallo's purported 'discovery' of 'the AIDS virus'
was announced at a press conference by him and HHS
Secretary Margaret Heckler on 23 April 1984. This
press conference was a major factor in making people
accept unquestioningly that 'HIV is the AIDS virus'.
So was a Lasker award to Gallo, Essex and Montagnier
in 1986 'for Leadership in Research on the Retrovirus
That Causes AIDS and Contributions Toward Under-
standing this World Wide Public Health Threat'.
2. What do people mean by 'AIDS'?
There does not even exist a single proper definition
of AIDS on which discourse or statistics can reliably
be based. Indeed, certain practices of the Centers for
Disease Control (CDC) obstruct a scientific appraisal
of the AIDS situation. The CDC definition of AIDS is
circular. It involves a list of24 to 29 diseases (depend-
ing on the year), about 60% of which have to do with
immunodeficiency (including tuberculosis), and 40%
have to do with other types of diseases, some of which
are of cancer type, such as cervical cancer (included
in 1992-1993), or Kaposi's sarcoma. The CDC calls
these diseases AIDS only when antibodies against HIV
are confirmed or presumed to be present. I If a person
I For instance, in the publication Confronting AIDS Update by
the Institute of Medicine (1988), we find:
p. 207: 'The following revised case definition for surveillance
of acquired immunodeficiency syndrome (AIDS) was developed by
CDC in collaboration with public health and clinical specialists ...
The objectives of the revision are a) to track more effectively the
severe disabling morbidity associated with infection with human
immunodeficiency virus (HIV) .. .'
p. 208: 'For national reporting, a case of AIDS is defined as an
illness characterized by one or more of the following 'indicator'
diseases, depending on the status of laboratory evidence of HIV
infection, as shown below'.
The updating occurs in the CDC publication Morb. Mort. Weekly
Rep. 41 No. RRl7 (I December 1992), giving 'the revised classi-
tests HIV negative, then the diseases are given another
name. Statistics based on such a definition are very
misleading, because the definition assumes the corre-
lation. Furthermore, some statistics from some sources
are based on the CDC definition, while others are not.
What good are statistics obtained or reported under
such circumstances? For example, to what extent did
the inclusion of cervical cancer and tuberculosis in
the group of AIDS-defining diseases cause statistics to
show an increase in the rise of AIDS among hetero-
sexuals?
Just talking about the 'AIDS' situation is difficult
because there are at least four possible notions defining
AIDS differently for different people, namely:
(a) One definition, which is that of the Centers for
Disease Control, is that AIDS is anyone of a
list consisting currently of 29 diseases, which are
called AIDS if and only if the person is HIV pos-
itive. About 40% of these diseases do not involve
immunodeficiency (e.g. cervical cancer).
(b) A second notion is that of an HIV-positive person
who has a disease such that the person is wasting
away, getting thinner, generally breaking down,
and dying.
(c) A third notion is that of a person who is HIV posi-
tive, currently without any symptoms of a disease,
but it is assumed that the person will be dying of a
disease as in case (b), in ten years, more or less.
(d) A fourth notion is that of a person who has currently
(or had) a severe case of irreversible immunodefi-
ciency, and is dying (or died) of immunodeficiency.
I shall attempt to make the distinctions clear in what
follows, and I ask readers to exercise great caution and
critical judgment when they are faced with material
in the U.S. media concerning the nature and cause of
AIDS. Readers should note that in many instances (and
practically all instances which have come to my atten-
tion), being HIV positive is identified in U.S. newspa-
pers with having AIDS (whatever AIDS is). So-called
'news' articles usually do not make clear whether this
means being sick and having severe immunodeficiency
fication system for HIV infection and expanded surveillance case
definition for AIDS .. .'. This document asserts:
p. 1. 'The etiologic agent of Acquired Immunodeficiency Syn-
drome is a retrovirus designated Human immunodeficiency virus
(HIV) .. .'
p. 2. 'Persons with AIDS-indicator conditions (Category C) as
well as those with CD4+ T-lymphocyte counts <200 ILL (Categories
A3 or B3) will be reportable as AIDS cases .. .'
p.4. 'Diagnostic criteria for AIDS-defining conditions included in
the expanded surveillance case definition are presented in Appendix
C .. .', which contains the 29 diseases, including Kaposi's sarcoma.

symptoms, or having one of the other diseases listed
by the CDC as an AIDS-defining disease (in the pres-
ence of mY), or whether it means being mv positive
while not having any diseases, but implying that AIDS
(whatever it is) will come in some unspecified time and
cause the death of the persons involved.
Example: A New York Times editorial. Most New York
Times 'news' articles that I have seen do not make the
distinction between HIV and AIDS clear. These news
articles are written as if 'AIDS' had a well-defined
universal meaning, which it does not, as I have point-
ed out. In any case, these articles assume that 'HIV
is the cause of AIDS' (whatever AIDS is), as in the
editorial 'Unyielding Aids', 13 August 1994, which
stated: 'The latest estimates from the World Health
Organization suggest that some 17 million people have
been infected so far with the AIDS virus and around
4 million have developed the disease'. However, this
sentence is defective in several ways.
First, use of the definite article ('the' disease) is
misleading, because there is no single disease invol ved,
according to the CDC.
Second, r~porting world-wide 4 out of 17 million
who have developed 'the disease' lumps together so
many factors and is subject to so many objections (see
§3 below) as to cause serious misrepresentations.
Third, Richard Strohman wrote to the Times (13
August 1994) about their editorial referring to 'the
AIDS virus':
But this is a misdefinition ... We all need to rec-
ognize that there is no AIDS virus; there is only
mv. To date the scientific community is agreed
that there is still no proven mechanism of causality
linking HIV and AIDS. The NY Times' responsi-
bility is to report accurately; it has not, and until
it does its readers remain unprepared to support
alternative approaches to AIDS causality, preven-
tion and cure ...
You also refer to the analogy in the fight against
cancer. It is apt. The war on cancer initiated
by President Nixon was declared as a war pretty
much against viruses as a main cause. The war
was declared lost years ago by most thoughtful
biologists. Especially with the powerful evidence
proving that cigarette smoking causes lung cancer,
scientists turned to research seeking further envi-
ronmental linkages ... If we could fully extend
the analogy of cancer to AIDS we would create
research possibilities far beyond the narrow view
275
of virus-only causality which by itself has spent bil-
lions and saved not a single life. Accurate reporting
on the current state of AIDS can do no harm and
could open all readers to possibilities not contained
in the present misdefinition.
Strohman's letter to the editors was not published.
3. HIV and AIDS
Some scientists, including especially Peter Duesberg,
for several years have challenged the hypothesis that
'HIV is the cause of AIDS', and have provided some
evidence for their challenge. In the past, I myself have
sometimes used the expression 'AIDS virus' in refer-
ring to HIY. In light of existing documentation, all such
references should be amended to contain the qualifi-
cation 'alleged'. At the time this essay is written, 1
do not regard the causal relationship between mv and
any disease as settled. 1 have seen considerable evi-
dence that highly improper statistics concerning HIV
and AIDS have been passed off as science, and that
top members of the scientific establishment have care-
lessly, if not irresponsibly, joined the media in spread-
ing misinformation about the nature of AIDS and its
connection with HIV or its connection with the use
(possibly repeated use) of certain drugs. Specifically:
1. No scientific piece of evidence. Some scientists
(including Peter Duesberg and Kary Mullis, indepen-
dently), have pointed out that there is no scientific piece
of evidence showing that HIV causes any disease. For
instance Kary Mullis is quoted in an interview (Cali-
forniaMonthly, September 1994 p. 20):
What happened was so simple I don't understand
why it never happened to other people. In the late
1980s, 1 was working for several companies that
were using PCR to detect HIV sequences. I would
get into a situation where I'd have to write a little
report on what was going on at one of the com-
panies. And I would find myself in a position of
having to write a sentence that said, 'HIV is the
probable cause of AIDS'.
I figured there must be a standard reference or
two I could use to back up that statement. So 1
just yelled across the room, 'What's the reference
for 'mv is the cause of AIDS' '? Some guy said,
'Oh you don't need a reference for that. Everybody
knows that'. And I said, 'I think it should be foot-
noted. When you make a direct statement like that,
276
you give a source. You say, 'Here's how I know
that's true'. I think it's good form'.
So he said, 'Why don't you cite this Centers for
Communicable Diseases [CDC] report?' He gave it
to me. It was a stupid little thing, without scientific
merit; you might as well quote the New York Times.
So I went to other people in the lab, and I started
looking at the scientific literature, and I began to
notice that nobody ever quoted a scientific paper to
back up the notion that HIV causes AIDS.
Both Duesberg and Mullis have emphasized that the
papers of Montagnier, Gallo or others do not provide
any scientific justification that HIV causes a disease.
They asked for such papers but none was forthcoming.
In his California Monthly interview, Mullis tells how
he began to think there was 'something fishy' about
the evasive answers he was getting to his questions.
He tells about the way he confronted Montagnier in
San Diego, after Montagnier had given a talk on AIDS.
Mullis 'noticed that Montagnier hadn't said one word
about how come we ought to think HIV is the cause of
AIDS'. After the talk Mullis asked Montagnier directly
for a scientific reference, and Montagnier admitted that
none existed.
Duesberg wrote a letter dated 11 February 1993,
to Harold Jaffe, Director of the HIV/AIDS Division
at the CDC. In that letter, Duesberg asked: 'Exactly
which papers are now considered proof or, if there is
no proof, the best support for the HIV-AIDS hypoth-
esis?' Not a single specific paper was mentioned in
Jaffe's reply. Jaffe only gave what he viewed as epi-
demiological evidence.
2. The case of chimpanzees. From 1983 to the late
eighties, 150 chimpanzees were infected with HIV, but
did not become sick as of 1994. This information was
obtained by Duesberg directly from Jorg Eichberg, cf.
Duesberg's article 'AIDS acquired by drug consump-
tion and other noncontagious risk factors', Journal of
Pharmacology and Therapeutics [referred to as Phar-
mac. Ther.] Vol. 55 (1992), pp. 203 and 211. Like
humans, chimpanzees are susceptible to HIY. The virus
replicates in them and antibodies form against it exact-
lyas in human beings.
3. What does HIV-positive mean? A difficulty lies in
determining who is 'HIV positive' and what HIV posi-
tivity means. The blood test for HIV does not determine
directly the presence of the virus. At best it determines
only having antibodies to the virus called HIV, and this
blood test is not infallible.
Furthermore, Duesberg has brought to my attention
scientific papers showing that antibodies to the influen-
za virus, tuberculosis bacillus, and leprosy bacillus
have each been shown to give false HIV positivetests. 2
Such findings were reported in various places, espe-
cially the London Sunday Times (,Research disputes
epidemic of Aids', 22 May 1994, p. 24), where its
science editor Neville Hodgkinson wrote:
An authoritative new study has uncovered pow-
erful evidence that the 'AIDS test' is scientifically
invalid, misleading millions into believing they are
HIV positive when they are not infected with the
virus.
The findings, published in the Journal ofInfec-
tious Diseases, provide practical evidence that HIV
tests may be triggered by other factors, such as lep-
rosy and tuberculosis. They have heightened con-
cerns that the spread of AIDS in Africa has been
wildly exaggerated.
The discovery was made by a team headed by
Dr. Max Essex of Harvard University's School of
Public Health and a highly respected AIDS expert.
One of the originators of the hypothesis linking
HIV with AIDS, Essex was also a leading exponent
of the theory that the virus originated in Africa.
Kary Mullis has also been quoted about HIV-
positivity in the context of 'African AIDS': ' ... They
got some big numbers for HIV-positive people [in
Africa] before they realized that antibodies to malar-
ia - which everyone in Africa has - show up as
2 Duesberg gives the following references:
- for the Hue, Mac Kenzie, W.R., Davis, J.P., Peterson, D.E.,
Hibbard, AJ., Becker, G. and Zarvan, B.S., 'Multiple false-positive
serologic tests for HIV, HTLV-l, and Hepatitis C following Influenza
vaccination',J. Am. Med. Assoc. 268 (1992) pp. 1015-1017.
- for tuberculosis, Pitchenik, A.E., Burr, ].J., Suarez, M., Fertel,
D., Gonzalez, G. and Moas, C., 'Human T-celilymphotropic virus-
III (HTLV-I1I) seropositivity and related disease among 71 consec-
utive patients in whom tuberculosis was diagnosed: a prospective
study', Am. Rev. Respir. Dis. 135 (1987) pp. 875-879.
- also for tuberculosis, St. Louis, U.E., Rauch, KJ., Peterson,
L.R. et aI. 'Seroprevalence rates of human immunodeficiency virus
infection at sentinel hospitals in the United States', N. Eng. J. Med.
323 (1990) pp. 213-218.
- for leprosy, Kashala, 0., Marlink, R., I1unga, M., Diese, M.,
Gormus, B., Xu, K., Mukeba, P., Kasongo, K. and Essex, M.,
'Infection with Human Immunodeficiency Virus Type 1 (HIV-I) and
Human T Cell Lymphotropic Viruses among Leprosy Patients and
Contacts: Correlation between H1V-I Cross-Reactivity and Anti-
bodies to Lipoarabinomannan', J. Inf. Dis. 169 (1994) pp. 296-304.

'HIV-positive' on tests'. (Interview in the California
Monthly, September 1994, p. 21)3
4. HIV-negatives with AIDS-defining diseases. There
exist thousands of Americans who have AIDS-defining
diseases but are HIV negative. It is quasi impossible to
give proper statistics about how many thousands, part-
ly because of the multiplicity of diseases used to define
'AIDS', and also because of the lack of studies which
would systematically report overall figures, either for
individual diseases or all of them as a group.
5. HIV-positives without diseases. Conversely, there
are hundreds of thousands who test HIV positive but
have not developed AIDS-defining diseases. As noted
by the magazine SPY (February 1993, p. 19), since
1985, the CDC has stated each year that there are
approximately one million Americans who are HIV
positive. The CDC figure remained constant from 1985
to 1993. But most of these people have not gotten
sick with one of the diseases listed by CDC in defin-
ing AIDS. Responding to Duesberg's letter dated 11
February, 1993, Harold Jaffe replied on 5 March 1993
that, of these one million, 'approximately 900 000 have
not developed one of the clinical conditions included
in the 1987 AIDS case surveillance definition'. So in
1993, the CDC was asserting that about 90% among
HIV positives have not developed an AIDS-defining
disease.
Jaffe's percentage figure is quite different from the
figure attributed by the New York Times to the World
Health Organization. The numbers game still goes on,
as reported for instance in a New York Times article
'Obstacle-Strewn Road to Rethinking the Numbers on
AIDS' (1 March 1994, p. B8), by Lawrence K. Alt-
man, M.D., who regularly writes on HIV and AIDS for
the Times, and systematically calls HIV 'the virus that
causes AIDS'. The article started: 'Determining how
3 Duesberg provided me with the following references for anti-
bodies against malaria registering as false-positive for HIV:
Biggar, R.I., 'Possible nonspecific associations between malaria
and HTLV-IIIILAV' , N. Eng!. 1. Med. 315 (1986)p. 457.
Biggar, R.I., Gigase, P.L., Melbye, M., Kestens, L., Sarin, P.S.,
Bodner, A.J., Demedts, P., Stevens, W.I., Paluku, L., C., D.H. et al.,
'ELISA HTLV retrovirus antibody reactivity associated with malar-
ia and immune complexes in healthy Africans', Lancet 2 (1985)
pp. 520-523.
Volsky, D.I., Wu, Y.T., Stevenson, M., Dewhurst, S., Sinangil,
F., Merino, F.L.R. and Godoy, G., 'Antibodies to HTLV-IIIILAV in
Venezuelan patients with acute malarial infections [letter]', N. Eng!.
J. Med. 10 (1986) pp. 647-648.
277
many Americans are infected with the virus that caus-
es AIDS is an imprecise science at best ... it appears
that the current estimate of one million will be low-
ered ... For planning purposes, health officials need
to know where and how many new cases of HIV, the
virus that causes AIDS, are occurring'. In his article,
Altman gave a revised figure ranging from 600 000 to
800 000, and reported that the figures might go down
further.
Note that the figure of 1 million 'estimated cumu-
lative HIV infections' in North America has also
been given by the World Health Organization ('The
HIV/AIDS Pandemic 1993 Overview', The WHO,
June 1993). This figure and other WHO figures for
Western Europe (500000) and Sub-Saharan Africa (8
million) were reproduced in a table prominently dis-
played in the article 'HIV: beyond reasonable doubt'
(The New Scientist, 15 January 1994, p. 24).
Just what is 'beyond reasonable doubt'? Consider-
ing the way some estimated numbers are now dropping
radically, it follows that official figures from the CDC
or WHO cannot be trusted. The figures these organi-
zations put out add to the chaotic and unreliable mess
which exists in lieu of information about HIV and var-
ious diseases.
6. Hemophiliacs. Questions have also arisen about
AIDS being transmitted to hemophiliacs via blood
transfusions. Such questions were raised for example
in Peter Duesberg's letter to Harold Jaffe. Duesberg
was careful about distinguishing HIV from diseases
presumed to have been caused by HIV. He wrote:
It is frequently claimed that transfusion AIDS was
eliminated by eliminating HIV from the nation's
blood supply. Of course, screening for HIV did
essentially eliminate the transmission of this virus
by transfusions. But it did not affect the mortali-
ty and morbidity of recipients of transfusions. We
must here distinguish between non-hemophiliacs
and hemophiliacs ...
(a) Non-hemophiliacs. Since all transfusion recipi-
ents, other than hemophiliacs, are already severely
ill by the time they receive their transfusions, the
mortality rates ofHIV-positives and negatives pro-
vide the most objective statistics on the possible
role ofHIV as a cause of diseases. In the rare cases
where such controlled studies have been done, the
mortality has been the same for both groups ...
(b) Hemophiliacs. The mortality of American
hemophiliacs has actually decreased since 75%
278
(some 15000) of them were infected by HIV via
transfusions received over a decade ago ... As for
the incidence of immunodeficiency in hemophili-
acs with and without HIV, at least 16 controlled
studies comparing these incidences have shown
that immunodeficiency is independent of HIV, but
depends on the lifetime dose of transfusions and
factor VIII ...
See also Duesberg's comments on hemophiliacs in his
Pharmac. Ther. paper, pp. 216-220, as well as an
exchange concerning hemophiliacs at the AAAS meet-
ing mentioned in §4 below.
Furthermore, among other places, a London Sunday
Times editorial taking to task some of the establishment
press for not reporting properly on the AIDS situation,
had this to say about the case of hemophiliacs (12
December 1993): 'Nature should also be discussing
the remarkable story of the HIV positive hemophiliacs
whose immune systems, after declining for many years
in ways that were attributed to HIV, have recovered
fully after they are switched to a new form of treatment
for their blood-clotting disorder. There now seems no
reason why they should not live a normal lifespan,
regardless of their HIV status'.
As for Kary Mullis, in his CaliforniaMonthly inter-
view, he said: 'The IV-drug users are exchanging blood
all the time, so they're getting everybody's diseases.
This was true for hemophiliacs too before recombinant
factor was available. If you're getting blood from lots
of other people, you're getting a lot of organisms along
with it'.
7. Different diseases in different risk groups. In addi-
tion, Duesberg's letter to Jaffe pointed out that peo-
ple in different risk groups in the United States come
down with different 'AIDS-defining' diseases. This
phenomenon provides evidence that those diseases do
not have a single cause, but different causes depend-
ing on different circumstances. For example, Duesberg
wrote that among patients who have 'AIDS-defining'
diseases according to the CDC, 'Kaposi's sarcoma is
almost totally restricted to male homosexuals; tubercu-
losis is prevalent in intravenous drug users; microbial
and fungal diseases, such as pneumonia and candidia-
sis, are practically the only AIDS defining diseases ever
observed in recipients of transfusions; finally, until the
most recent reclassification of diseases under the AIDS
umbrella on January 1, 1993, bacterial infections were
exclusively diagnosed in babies who were defined as
having AIDS according to the CDC ... '
8. Differences with Africa. Differences exist not only
internally within the United States, but also interna-
tionally. According to Duesberg ('The Last Word',
Biotechnology Vol. 11, August 1993, p. 956), 'since a
clinical definition is used in Africa, statistics [about
AIDS patients] from this continent are not biased
against HIV-free AIDS .. .' Duesberg cites several
specific studies about actual AIDS patients from Africa
which show that approximately 50% of the diagnosed
AIDS cases in these studies were HIV-antibody neg-
ative. Some of these patients suffered from diseases
such as weight loss, diarrhea, chronic fever, tubercu-
losis, and neurological diseases. Statistics about AIDS
patients in Africa also report equal distribution of AIDS
among male and female. Some studies showed that
HIV positivity did not precede but followed weight
loss by several months and possibly years. Furthermore
some diseases associated with specific risk groups in
the U.S. have not al ways been diagnosed as part of the
'AIDS epidemic' in Africa. For instance, the authors
of one study wrote: 'Since KS [Kaposi's Sarcoma] has
long been endemic in Zaire, only patients with fulmi-
nant KS were included,.4 Aside from alI that, we recall
that antibodies to malaria and other diseases prevalent
in Africa show up as HIV-positive on tests. Hence
the evidence suggests that whatever epidemic is taking
place in Africa is due to causes different from those
affecting the main risk groups in the U.S., such causes
possibly involving malnutrition, poor sanitation, and
other factors.
The article cited in footnote 4 evaluates critical-
ly the AIDS situation in Africa. In the abstract at the
beginning of the article, one finds: 'It is concluded
that both acquired immune deficiency (AID) and the
symptoms and diseases which constitute the clinical
syndrome (S) are long standing in Africa, affect both
sexes equally, and are caused, directly and indirectly,
by factors other than HIV' .
9. Destruction of T-cells? Even if patients have dis-
eases unrelated to immunodeficiency, the HIV-AIDS
hypothesis asserts that HIV affects the immune system
in some fashion, for instance by destroying T-cells,
thus making a person more liable to develop these oth-
4 For a more extensive account of such studies, see E.
Papadopulos-Eleopulos, Y.F. Turner, I.M. Papadimitriou, and Har-
vey Bialy, •AIDS IN AFRICA: DISTINGUISHING FACT FROM
FICTION', in press, World J. Microbiology & Biotechnology, 1995.
Bialy is research editor of Biotechnology, and was an active partic-
ipant at the AAAS Pacific Division meeting on HIV and AIDS, 21
June 1994; see below.

er diseases. However the available evidence does not
show that HIV destroys T-cells:
(a) There exist studies which show the existence of
patients who test HIV-positive, who have diseases
such as Kaposi's sarcoma, dementia, wasting dis-
ease, but who have a normal T-cell count, and have
no immunodeficiency. There exist similar stud-
ies when the patients are HIV-negative. Duesberg
gives examples of both in his article (Pharmac.
Ther. p. 228, referring to half a dozen independent
studies, listed in the bibliography). He concludes:
'Thus, the assumption that all AIDS diseases are
caused by immunodeficiency is erroneous'.
(b) As for HIV killing T-cells in laboratory cultures,
Duesberg draws attention to the fact that T-cells
are notoriously difficult to maintain alive, whether
infected with HIV or not. He gives scholarly refer-
ences to the effect that they are not more difficult
to maintain alive in the presence of HIV than in the
absence of HIV (Pharmac. Ther. p. 229). In addi-
tion, HIV is mass produced for the HIV antibody
blood test in permanently self reproducing T-cells,
in many laboratories and companies.
10. A correlation between HIV and AIDS? Support-
ers of the hypothesis that 'HIV is the cause of AIDS'
(whatever this means) rely on what they see as a 'cor-
relation', that antibodies to the HIV virus are present
in some (many? all?) people having AIDS (whatever
AIDS means). However there are several reasons for
reading whatever 'correlation' exists with caution.
(a) I have already commented on the circularity of the
CDC definition, which makes the correlation 100%
if this definition is accepted, and on the problem of
having meaningful statistics concerning the asso-
ciation of HIV with the multiple AIDS-defining
diseases in the CDC list if a clinical definition is
taken.
(b) Some people in the risk groups among which
the actual disease is prevalent engage in practices
whose effect is to increase the possibilities of pass-
ing on various viruses or microbes from one person
to another, whether these are pathogenic or not.
Among these viruses is HIV. Thus one explana-
tion for the more extensive presence of HIV in risk
groups lies in these practices. On the other hand,
the spread of the HIV virus or other viruses in cer-
tain groups (for instance prostitutes) by itself does
not necessarily correlate with this group being at
high risk for AIDS-defining diseases. For instance,
279
prostitutes who do get some AIDS-defining dis-
eases on the whole are also found to engage in other
practices besides sex, e.g. drug use (see Duesberg's
Pharmac. Ther. paper, p. 238).
(c) Although there is a correlation of lung cancer with
smoking, there is also a correlation of lung cancer
with yellow fingers. This does not imply that yel-
low fingers cause lung cancer. Even when a 'corre-
lation of HIV with AIDS' is claimed, there may be
another correlation which is even stronger, namely
between certain diseases and the use of drugs of
various sorts, ranging from recreational drugs such
as 'poppers' to purportedly HIV-inhibiting drugs
such as AZT (see §4 and §5 below). It may simply
be that HIV is an opportunistic virus which tends
to be present when some diseases are present. Thus
HIV would be merely a marker rather than a cause
for whatever disease is involved.
A number of other points raise questions about the
causal relationship between HIV and various diseases,
but I merely wanted to give a sample here. Of course,
none of the above points gives a conclusive answer as
to what causes AIDS, or what does not cause AIDS in
human beings, whatever AIDS is. I have no definitive
answer. I merely question the line upheld up to now
by the biomedical establishment, and repeated uncrit-
ically in the press, that 'HIV is the virus that causes
AIDS'.
The improper reporting in the press reflects defec-
tive statements from many scientists who promote the
establishment line about HIV being the cause of AIDS.
That 'HIV is the cause of AIDS' is taken as a postu-
late, and some scientists try to fit experimental data
into this postulate, actually without success. Some-
times they hedge by speaking of 'association' rather
than 'cause'. Sometimes they state that they are still
looking for 'the enigmatic mechanism of the patho-
genesis of HIV', which means they haven't found the
way HIV causes any disease and are still looking. So
how come they assert without qualification that 'HIV
is the cause of AIDS'?
4. Some revisionism
The 'drug hypothesis'. An alternative hypothesis con-
cerning a possible cause of some AIDS-defining
diseases is sometimes called the 'drug hypothesis'.
Roughly speaking, this hypothesis asks whether drug
use causes some of the diseases officially associated
280
with AIDS, such as immunodeficiency and Kaposi's
sarcoma. Various drugs could be involved, ranging
from sex-enhancing recreational drugs such as amyl-
nitrite ('poppers'), to cocaine or heroin, and also
allegedly HlV-inhibiting drugs such as AZT. The time
period and the cumulative effect may also be factors
involved in the causation. The situation may be similar
to prolonged use or abuse of alcohol causing cirrhosis
of the liver, or smoking causing lung cancer.
Originally, in the early eighties, the drug hypoth-
esis was among the first which occurred to scientists.
It was abandoned, or overlooked, or disregarded by
most establishment scientists in large part because of
the Gallo-Montagnier controversy, and the Gallo press
conference in 1984. It was never completely aban-
doned, even by some individuals in the CDC. For
instance, as late as 1988, the National Institute on Drug
Abuse (NIDA) published a monograph entitled 'Health
hazards of nitrite inhalants' dealing with many aspects
of the toxicity of nitrite inhalants. Harry Haverkos,
clinical director of AIDS research at NIDA, and co-
editor of the above monograph, still supports having
experiments made to test the nitrite-AIDS hypothesis.
However, research on causes for 'AIDS' other than
HIV has been obstructed in various ways, including
social and scientific pressure, and non-funding.
In 1993-1994, there was some evidence of a revi-
sionist movement which surfaced sporadically, partly
on TV, partly in some of the non-mainstream press in
the United States, and in other places. Thus some of the
media started reporting questions raised by some scien-
tists about the role of HIV in causing 'AIDS'. The year
1994 especially saw a continuing evolution in think-
ing about HIV, and what is regarded as appropriate for
mainstream publications. I shall list some examples of
media reports of the revisionist movement.
Peter Duesberg. In the last decade, Peter Duesberg has
been one of those who have continued to raise ques-
tions about the drug hypothesis seriously. For decades
he had been in high standing with NIH and had been
continuously funded, receiving 'outstanding investi-
gator' grants. After he spoke out clearly challenging
the dogma about HlV being 'the cause of AIDS', and
supporting the drug hypothesis, he lost his grants.
In 1992 he applied to the Department of Public
Health for funding for experiments to test the drug
hypothesis on animals (for instance, 'feed poppers to
mice' as he once said in picturesque language).
Duesberg's application was supported by the editor
of Science, Daniel Koshland, who wrote to the Study
Section of the National Institute on Drug Abuse to urge
the funding (26 August 1993), stating in part: 'As an
observer, I have in the past been critical of Duesberg
for not suggesting experiments to resolve this contro-
versy. However, he has now answered my call with a
proposal to test the role of nitrite inhalants as a cofac-
tor in AIDS ... Duesberg's proposal is a specific,
workable one that will be done in collaboration with
an inhalation toxicologist at the University of Califor-
nia, Davis. I believe this research would add much to
our understanding of AIDS, and I have told Duesberg
that I would consider such data important material for
readers of Science if it develops appropriately' . In fact,
Koshland iterated his support for funding Duesberg's
experiments a year later, in a letter dated 24 August,
1994.
Duesberg was not funded. He received a notice stat-
ing (13 December 1993): 'The Initial Review Group
(lRG) has recommended that NO FURTHER CON-
SIDERATION BE GIVEN TO THIS APPLICATION.
[Capital letters in the original.] Applications so des-
ignated cannot be funded in their current form; there-
fore they are not routinely scheduled for second-level
review by the National Advisory CounciUBoard .. .'
(See my essay 'To fund or not to fund .. .' for details).
Science did not report on the situation, despite the inter-
est expressed by its editor.
A meeting sponsored by NIDA; report in Biotechnol-
ogy. On 23 and 24 May 1994, the National Institute
on Drug Abuse (NIDA, Rockville MD) sponsored a
meeting on the toxic effects of nitrite inhalants. This
meeting was not covered by Science and the New
York Times, for example. The 12 August 1994 issue
of Biotechnology reported on this meeting under the
headline: 'NIH reconsiders nitrites' link to AIDS'. A
displayed conclusion of the article stated: 'A consen-
sus is developing that the connection between nitrites
and AIDS goes beyond their promoting of HlV trans-
mission and that understanding nitrite toxicity should
be a priority of AIDS research'.
The article, by John Lauritsen, stated among other
things:
Meeting participants were divided into those whose
primary interest is in studying nitrite inhalants as an
important risk factor for AIDS, because their use
encourages transmission of HIV via unsafe sex,
and into those who think that the mutagenic and
carcinogenic nitrites function more directly, either
causing AIDS alone or acting as cofactors of HIV.

Both sides were supported by strong epidemiologi-
cal correlations between nitrite use by male homo-
sexuals and AIDS. For example, according to Jay
Paul of the University of California at San Fran-
cisco, the highest risk for AIDS involves the use
of poppers and four other drugs. And Lisa Jacob-
son of Johns Hopkins University (Baltimore, MD)
reported that 60-70 percent of the several thou-
sand gay men at risk for AIDS who participated in
the Multicenter AIDS Cohort Study (MACS) have
used nitrites.
In addition, those favoring a more direct role
of nitrites in AIDS pointed to data from the MACS
showing that HIV-negatives had, on average, 25
months of nitrite use, HIV-positives had 60 months
of nitrite use, and AIDS patients had over 65
months of nitrite use - an apparent dose-response
relation. When asked whether there was even one
gay AIDS case in the cohort who had not used
drugs, a somewhat-surprised Jacobson replied, 'I
have never looked at the data in this way'.
Jacobson's answer documents the extent to which
researchers have shut out questions which did not
fit into the establishment dogma about HIV being
the virus that causes AIDS, to the exclusion of oth-
er hypotheses in general, and the drug hypothesis in
particular.
Lauritsen's article in Biotechnology also report-
ed several other studies linking nitrites to AIDS,
notably:
Harry Haverkos, acting director for clinical
research at NIDA and chairman of the meeting,
extended his original observations on the role of
poppers in gay AIDS and reported an essentially
exclusive correlation between nitrite use and gay
KS [Kaposi's Sarcoma]. The hypothesis of Harold
Jaffe of the CDCP [Centers for Disease Control
and Prevention] that an 'unknown infectious agent'
is the cause of KS could not be reconciled with
Haverkos' evidence that there was not a single con-
firmed case of KS from blood transfusions, which
often contain infectious agents.
SPIN. Celia Farber wrote a number of articles on the
developing AIDS revisionism in the magazine SPIN,
for instance 'AIDS - WORDS FROM THE FRONT',
10 January 1994, p. 71, where she reported:
281
In 1993, we witnessed a dizzying spectacle of col-
lapsing certainties and quick political repositioning
around the subject of AIDS ...
This year, however, the editor of Science
[Daniel Koshland] wrote a letter to the National
Institute of Drug Abuse, requesting that Duesberg
be funded to test his drug hypothesis.
The mainstream [U.S.] press has remained
largely oblivious to the HIV debate, and the pro-
gressive liberal press (Village Voice, etc.) strictly
shrill, anti-debate, and ill-informed as ever. Yet
major network television proved to be surprising-
ly progressive in 1993. In March, ABC aired a
groundbreaking half hour segment on the program
Day One, on which they interviewed Duesberg,
Dr. Joseph Sonnabend, Dr. Robert Root-Bernstein,
Walter Gilbert, and other HIV skeptics. Gallo threw
an on-camera tantrum, storming off the set when
asked about Duesberg, fuming that the reporters
were doing a 'grave disservice to the American
public'.
The article goes on:
But perhaps the single most important event of
1993 was the release of the much awaited Concorde
trial, which showed that AZT does not prolong life
or improve health in people who are HIV-positive
but still healthy.5 Former AZT supporters leaped
from the sinking ship ... The Group for the Scien-
tific Reappraisal of the HIV/AIDS Hypothesis had
a 1000 percent increase in signatures following the
release of the Concorde results . . . In October,
one of the group's long-standing members became
a Nobel Laureate in chemistry: Dr. Kary Mullis,
inventor of the gene-amplification technique Poly-
merase Chain Reaction (PCR). PCR is one of the
main biological tools used in AIDS research. But
a fact that is virtually never reported is that Mullis
is an HIV skeptic. In 1991, speaking on the record
for the first time, Mullis told SPIN, 'PCR made it
easier to see that certain people are infected with
HIV, and some of those people came down with
symptoms of AIDS. But that doesn't begin, even,
5 There are indications that mortality in the AZT group was sub-
stantially higher than in the placebo group. An editorial analysis is
given in The Lancet, 7 August 1994 under the title: 'Zidovudine for
mother, fetus, and child: hope or poison'. 'Zidovudine' is another
name for AZT. Duesberg has also pointed to the toxic effects of AZT.
So did Kary Mullis in his California Monthly interview, where he
said that 'most people who have HIV don't ever get AIDS, although
people who have HIV and no symptoms and take AZT die ... But
they die from the poison AZT, not from AIDS'.
282
to answer the question, 'Does HIV cause itT'
Celia Farber published an interview with Kary
Mullis in the 4 July 1994 issue of SPIN, from which I
quote.
Our talk focused on AIDS. Though Mullis has not
been particularly vocal about his HIV skepticism,
his convictions have not, to his credit, been mud-
dled or softened by his recent success and main-
stream acceptability. He seems to revel in his newly
acquired power. 'They can't pooh-pooh me now,
because of who I am', he says with a chuckle -
and by all accounts, he's using that power effec-
tively ... 6
When ABC's Nightline approached Mullis
about participating in a documentary on himself,
he instead urged them to focus their attention on
the HIV debate. 'That's a much more important sto-
ry', he told the producers, who up to that point had
never acknowledged the controversy. In the end,
Nightline ran a two-part series, the first on Kary
Mullis, the second on the HIV debate. Mullis was
hired by ABC for a two-week period, to act as their
scientific consultant and direct them to sources.
The show was superb, and represented a historic
turning point, possibly even the end of the seven-
year media blackout on the HIV debate ...
6 Actually, Mullis in April 1994 was at a scientific meeting in
Europe, where he is reported to have acted like a jerk. Cf. a letter
to Nature by John F. Martin, President of the European Society for
Clinical Investigation, Nature 371, 8 September 1994. His capacity
for acting like a jerk (his own word) was mentioned in his Cali-
fornia Monthly interview. Nobody I know is hiding this aspect of
his personality. My conclusion about dealing with Kary Mullis is to
separate what he does on a personal basis, and which has sometimes
been objectionable, from the insights he provides as a scientist when
he's not behaving like ajerk.
He does not always act like a jerk at meetings, for instance at
the Pacific Division AAAS meeting (see below), where he raised
perfectly valid questions. The answer which Kary Mullis gave to
the quote from Baltimore, extracted at the beginning of this article,
was very sensible, to the effect that what he believes about AIDS
is irrelevant, because beliefs have to do with religion, and we are
attempting to deal with science. What is scientifically relevant is
what documentation is available about the nature of HIV and its
effects, and what documentation is available about various diseases
and antibodies for certain viruses or bacilli.
It is unfortunate that in addition to all other problems one is facing
in the confrontation about HIV and AIDS, one has to cope with the
personal behavior of a scientist who had enough insight to discover
peR. It is left for participants in the HIV-AIDS debate to sort out
the personal behavior from the scientific one.
Celia Farber also mentioned the hypothesis that
Kary Mullis has concerning the breakdown of the
immune system in some of the risk groups: 'Kary
Mullis hypothesizes that AIDS is not caused by any
single organism, but by prolonged exposure to an over-
whelming number of distinct organisms, which indi-
vidually may he harmless.'
Harry Haverkos. In November 1994, SPIN published
a four-page article on Harry Haverkos, who was chair-
man of the NIDA meeting. I quote from this article:
Surrounded by stacks of medical journals in his
cramped office, Haverkos gives four main reasons
why he links KS with nitrite use. First, there is
the statistical connection. Repeated use of poppers
and incidence of KS have been confined to gay
men. 'About 96 percent of Kaposi's cases occur
in gay men, who make up 65 percent of all AIDS
cases', he says. Twice as many whites as blacks
use poppers - and twice as many get KS ...
Second, there is the lack of a firm HIV con-
nection to KS. No cases of KS have been report-
ed among blood-transfusion recipients where the
blood donor himself later developed the cancer ...
The third reason Haverkos suspects a nitrite
connection to KS is that the disease is caused by
an abnormal growth of blood vessels, and nitrites
act on blood vessels ...
Finally, Haverkos says, 'The KS lesions are
most common on the face, nose, and chest. If
you're inhaling vapors, that is where you will
have the highest concentrations'. Put those points
together, he says, and 'you don't have to be a rock-
et scientist to see that there is some logic to the
hypothesis' .
... Haverkos believes the government's unoffi-
cial position today is that mv may not be involved
in KS, but whatever is, is transmitted sexually;
the unwritten rule of public health seems to be
that infectious diseases always trumps toxicolo-
gy. Haverkos argues: 'If somebody could find me
five white women with Kaposi's who did not use
nitrites, between the ages of 18 and 45, sexually
linked to a man with Kaposi's - just five couples
- that would take me back. But we're 13 years
into this epidemic, and I have not seen such cases
reported. If this was a sexually transmitted agent,
there ought to be a handful of women like that' .

Once again, one finds such analyses from a 'lone
crusader at the National Institutes of Health' (as SPIN
calls Haverkos) in SPIN, but not in Science or the New
York TImes, or the other major scientific or main-stream
newspaper and magazines.
Aside from chairing the NIDA meeting, being a
co-editor of the NIDA monograph on nitrite inhalants
mentioned previously, and airing his views in SPIN,
Haverkos is also the author and co-author of several
articles over more than a decade, such as 'What causes
Kaposi's Sarcoma? Inquiring Epidemiologists Want to
Know' , co-authored with Peter Drotman (Epidemiolo-
gy, May 1992 Vol. 3 No.3, pp. 191-193). This article
stated three hypotheses concerning causes of KS: '(1)
a particular strain of HIV causes Kaposi's sarcoma;
(2) another infectious agent acts as a cofactor; and (3)
a nonbiological environmental agent acts as cofactor
[ofHIV]' . The article immediately stated that 'the first
hypothesis has been disproved .. .' However, the arti-
cle also discarded the possibility that some factors may
be independent of HIV by calling the other two 'cofac-
tors'. Asking whether something is a cofactor of HIV
prejudices the question in one direction. One can see
this by reordering the question. Asking whether HIV is
a cofactor of nitrite inhalants, in the absence of definite
confirmation that they cause KS, would prejudice the
question in the other direction, implicitly granting that
nitrite inhalants are a factor. With either formulation,
the use of the expression 'cofactor' is prejudicial to an
impartial investigation of possible causes of KS.
Since KS is endemic in some countries of Africa,
and nitrite inhalants are not a cause in that country, it
follows that nitrite inhalants are certainly not a neces-
sary cause of KS, although there is evidence that they
are sufficient, taken in sufficiently strong doses over a
sufficiently long period of time. Haverkos himself is
one of those who have emphasized this evidence, as
reported in SPIN and in the Epidemiology article. In
this article, the authors also state that 'the epidemic pat-
tern of Kaposi's sarcoma in the industrialized nations
does not fit that of any other sexually transmitted dis-
ease. All the others te~d to be prominent in minority
racial/ethnic groups, particularly urban blacks and His-
panics, whereas epidemic Kaposi's sarcoma tends to
occur in middle-class whites'. In addition, it is rele-
vant to note here that clinical symptoms of Kaposi's
sarcoma in Africa and in the gay groups in the United
States have been reported to be different, for instance
with respect to the location of the lesions.
Given the current state of knowledge, it is illegiti-
mate to discard a priori the possibility of factors for KS
283
independent of HIY. The Drotman-Haverkos article
gave no reason for having done so, or for having preju-
diced investigations and discourse about possibly inde-
pendent causes for KS in the direction of 'cofactors' of
HIV. In their article, they mention 'six large cohort or
case-control studies'. Subsequently, they do not make
clear whether these studies considered and tested for
the possibility of factors such as nitrite inhalants to be
independent of HIV, or if it was assumed automati-
cally that they are 'cofactors' of HIY. The Drotman-
Haverkos article legitimately criticized some of the
questionnaires used in these studies, in a way which
makes them appear partly incompetent or sloppy, but
the reader was given no information:
- to determine if these studies implicitly assumed
that HIV is a cause of KS;
- to determine if these studies tested whether HIV
occurs as a marker, or whether it is a cause;
- to determine if these studies were designed to test
whether KS occurs independently of HIV antibod-
ies positivity, or to what extent.
London Sunday Times. Perhaps the most spectacular
revisionist event was the publication of a series of arti-
cles in fall 1993 by the London Sunday Times, which
also quoted Kary Mullis in the Sunday Times editorial
(12 December 1993): 'The HIV theory, the way it is
being applied, is unfalsifiable and therefore useless as
a medical hypothesis ... If there is evidence out there
that HIV causes AIDS, there should be some scientific
documents which either singly or collectively demon-
strate that fact, at least with a high probability. There
is no such document' .
The Sunday TImes series of articles was virulently
attacked by some of the medical and scientific estab-
lishment, especially in editorials by Nature's editor
John Maddox, such as the one of 9 December 1993.
The Sunday TImes science editor Neville Hodgkinson
replied equally vigorously on 12 December 1993. His
reply began:
The Sunday Times has been subjected to a wave
of extraordinary attacks in recent weeks over its
attempts to widen discussion of one of the most
crucial medical and scientific issues of our time,
the cause of AIDS.
A growing body of evidence suggests that when
the medical and scientific communities rallied in
1984 behind a call to arms against the Human
Immunodeficiency Virus (HIV) as the purported
cause of a terrible new syndrome afflicting homo-
284
sexuals and drug-users, they may have picked the
wrong target.
This sensational possibility, now being con-
templated by numerous doctors, scientists and oth-
ers intimately concerned with the fight against the
disease, deserves the widest possible examination
and debate. Yet it has been largely ignored by the
British media and suppressed almost entirely in the
United States.
The Sunday Times also wrote: 'We look forward
to seeing Nature open its pages to the views of the
distinguished scientist [Kary Mullis], who received the
[Nobel] prize for a genetic test now used worldwide
by AIDS researchers'.
The New York Times is among the newspapers
which has not given examination and debate for the
above 'sensational possibility'. However, it did report
the existence of the controversy between the Sunday
Times and Nature in the article 'British Paper and Sci-
ence Journal Clash on AIDS', even though it did not
report the substance of the documentation presented
either by the Sunday Times or its critics'?
Hodgkinson in his articles had pointed to some
instances when Maddox did not publish pieces going
against the hypothesis that HIV is the AIDS virus. On
one occasion when Maddox did not publish such a
piece, his position was summarized as follows ('Has
Duesberg a right of reply?', editorial in Nature 363, 13
May 1993, p. 109): 'The truth is that a person's 'right
of reply' may conflict with a journal's obligations to
7 New York TImes, 10 December 1993, p. A9. Sample from this
article:
But the newspaper's latest crusade - a series of articles or promi-
nently displayed articles boldly arguing that the AIDS epidemic in
Africa is a myth and strongly suggesting that HIV is not the way
the AIDS infection spreads - has provoked bewilderment and anger
among some Government health officials, AIDS organizations and
many scientists, some of whom have accused The Sunday Times of
betraying the public trust and misleading its four million readers ...
Dissident theories on the putative cause of AIDS, including those
of Dr. Peter Duesberg, an American molecular biologist, have been
widely debated over the last decade and dismissed by most Govern-
ment and research organizations as scientifically unsound ...
In addition to Nature's stinging attack, The Sunday Times's cover-
age has prompted criticism from Governmentofficials, charities, and
relief agencies involved with AIDS. Kate O'Neil, a spokeswoman
for the Terrence Higgins Trust, Britain's largest AIDS charity, said
she agreed that newspapers have a responsibility to question any
orthodox view. 'But the problem is, they are not giving all the facts,
which means they are misleading some and giving others false', Ms.
O'Neil said.
Neville Hodgkinson, The Sunday Times's science editor and the
author of most of the stories, said the paper is serving the pub-
lic interest by telling readers that serious scientists and researchers
dissent strongly from the accepted view that HIV causes AIDS.
its readers to provide them with authentic information.
Whatever Duesberg's friends say,S the right of reply
must be modulated by its content' .
Furthermore, Maddox accused the Sunday Times
of 'selective reporting of the evidence' (among other
things). However, at a time when Nature itself refused
to print certain articles questioning the HIV causality
of AIDS, Hodgkinson stated: 'Despite distortions and
inaccuracies, the [Nature] editorial deserves a wider
audience than Nature's, both in the interests of open
debate and because ofthe insight it gives into the mind
of the journal's editor. So we reprint it in full below,
with Maddox's permission, though he requested £200
[about $300] for the privilege'.
A subsequent issue of the London Sunday Times
(3 April 1994) headlined: 'These scientists are among
hundreds now challenging the accepted view on AIDS.
But the establishment won't let them be heard'. Below
the photographs of ten scientists, accompanied by brief
quotes from each, the Sunday Times science editor
Neville Hodgkinson wrote:
... Scientists, too, have to be careful not to rock
the HIV boat, which carries jobs, reputations, and
huge research funds. Despite the pressure, a large
and growing network of highly-qualified 'dissi-
dents' has become established worldwide over the
past two years. They not only challenge the HIV
hypothesis, but have 'come out' publicly about
their concerns. More than 450 have put their names
to a letter demanding a reappraisal of the conven-
tional view, arguing that the HIV hypothesis is at
best unproven, at worst discredited ...
Most of the names are American-based, but
overall the list spans 23 countries.
It is the tip of an iceberg of dissent. The group's
newsletter has a mailing list of more than 2000 ...
Signatories of the reappraisal letter are united
in wanting a change in direction; they differ in the
extent to which they reject the HIV theory.
Some, like Dr. Charles Thomas, a molecu-
lar biologist and former Harvard professor of bio-
chemistry, say it is complete nonsense ...
Others, like Dr. Lawrence Bradford, a biology
professor in Atchison, Kansas, and Dr. Roger Cun-
ningham, a microbiologist and director of the cen-
8 The phrase 'whatever Duesberg's friends say' is an example
of Maddox's tendentious journalism. It contains an innuendo that
only Duesberg's friends raise questions about the right of reply. But
questions about the right of reply are independent of whether one is
a friend of Duesberg or not. See also footnote 13.

tre for immunology at the State University of New
York at Buffalo, think the virus could be one factor
among many, but maintain an unbiased reassess-
ment is urgently needed.
'Unfortunately', Cunningham says, 'an AIDS
'establishment' seems to have formed that intends
to discourage challenges to the dogma on one side
and often insists on following discredited ideas on
the other'.
... Most of the signatories, such as Dr. Henk
Loman, professor of biophysical chemistry at the
Free University in Amsterdam, deplore the neglect
of non-HIV lines of research ...
Many of the scientists believe the fight against
AIDS was derailed by a flaw in reasoning over HIV
in which 'the hypothesis itself got incorporated in
the definition of AIDS' as Dr. Kary Mullis, win-
ner of last year's Nobel prize for chemistry, puts
it. When people fall sick and HlV is present or
thought to be present, it is called AIDS; when HIV
is not present, it is called something else ...
Thus did the Sunday Times keep informing its read-
ers of the existence of a dissident group.
Root-Bernstein in The Scientist. On 4 April 1994, The
Scientist printed an article by Robert Root-Bernstein
entitled 'Agenda for U.S. AIDS Research Is Due For
A Complete Overhaul' . The article started on the front
page and extended over three pages inside the journal.
Among other things, Root-Bernstein asserted:
An example of something we thought we knew,
but did not, is that the human immunodeficien-
cy virus (HIV) is the direct cause of T-cell killing
in AIDS. Even such formerly stalwart proponents
of this notion as Anthony Fauci and Robert Gallo
now admit that this is not the case. Virtually all HIV
research is now focused on finding 'indirect' mech-
anisms by which HIV may cause immune suppres-
SIon.
We also thought we knew that HIV alone is suf-
ficient to cause AIDS. But such researchers as Luc
Montagnier, Shyh-Ching Lo, Joseph Sonnabend,
and many others - including me - now believe that
co-factors are necessary and, therefore, that HIV
by itself cannot cause AIDS.
We used to think we knew that everyone is at
equal risk for HIV and AIDS, and that a heterosex-
ual epidemic was inevitable. But the epidemiolo-
285
gy of AIDS has yet to prove consistent with that
view ...
We thought we knew that people in all AIDS
risk groups proceed to AIDS at the same rate fol-
lowing HIV infection, but this also has turned out
to be untrue ...
We thought we knew that HlV always precedes
immune suppression in people who develop AIDS.
But many studies show that lymphocyte counts are
as low in some HIV-negative gay men, intravenous
drug users, and hemophiliacs as they are in non-
symptomatic HIV-positive people - and sometimes
lower ...
Root-Bernstein concluded his article with the admoni-
tion:
A diversity of opinion and of research has never
hurt science. Dogmatism and politically motivat-
ed programs often have. The AIDS task force can
foster one or the other, but not both.
I urge people to compare this admonition with the
reactions of some establishment scientists, who have
tried, so far mostly successfully, to keep reports ques-
tioning the establishment dogma about HIV out of the
mainstream press. Sometimes they give as reason that
such questioning 'presents a danger to public health.
A divisional meeting ofthe AAAS. On 21 June 1994, the
Pacific Division of the American Association for the
Advancement of Science (AAAS) sponsored a meeting
- symposium - in San Francisco, to address: 'The Role
of HlV in AIDS: Why There is Still a Controversy'.
The symposium was organized by Charles Geshek-
ter, Professor of History at California State University,
Chico. The symposium and the list of speakers was
approved by the Executive Committee of the Pacific
Division, and announced in the 25 January 1994 Pacif-
ic Division newsletter. The symposium took place,
despite pressure on the AAAS in May 1994, by Nature
and by some scientists not to allow this symposium, or
to change its thrust, for instance in the article 'AAAS
criticized over AIDS sceptics' meeting' (Nature 369,
26 May 1994, p. 265).
- Nature's article started: 'The American Associ-
ation for the Advancement of Science (AAAS) has
come under fire from US AIDS researchers and public
health officials for its sponsorship of a meeting in San
Francisco next month of which speakers will dispute
286
the link between HIV and AIDS ... But as criticism of
the line-up mounted, AAAS executive officer Richard
Nicholson indicated that the session might be called
off. 'All options are still open, including cancellation' ,
Nicholson said on Monday' .
- Nature quoted Bernie Fields, professor of micro-
biology at Harvard Medical School: 'This is a real
fringe of people surrounding Peter Duesberg who have
been saying these things for a while now. AAAS spon-
sorship makes it sound like a real issue when it's not.
It thinks it's a disgrace'.
- Nature quoted David Baltimore: 'This is a group
of people who have denied the scientific facts. There
is no question at all that HIY is the cause of AIDS.
Anyone who gets up publicly and says the opposite
is encouraging people to risk their lives,.9 Howev-
er, Nature did not specify which 'scientific facts' are
'denied'. Furthermore the expression 'group of people'
is rather vague, and is sweeping in its characteriza-
tion possibly involving anyone who talks to Duesberg.
Hence the first sentence quoted above is defective on
several counts. In itselfthis sentence represents unsci-
entific behavior and tendentious journalism, both on
the part of Baltimore and on the part of Nature.
- Nature also quoted scientists from the Bay
area: 'Michael Ascher, of the California Depart-
ment of Health Services, and Warren Winkelstein, of
the University of California at Berkeley, have writ-
ten to the AAAS journal Science questioning the
AAAS sponsorship because 'some of the views to be
expressed ... have potentially serious adverse pub-
lic health consequences.' ' (For more on Ascher and
Winkelstein, see the next section.)
Subsequently, the AAAS meeting itself was not
covered by Nature. A fortiori, Nature did not report
the reasons some scientists gave for questioning that
'HIY is the cause of AIDS', so Nature's readers are
not given evidence on which to base an informed or
independent judgment. Thus does Nature manipulate
its readers.
Criticisms similar to those in Nature were made
in the San Francisco Chronicle under the tendentious
headline 'AIDS Rebels Try to Steal Show: But Scien-
tists Stymie Plan By Mavericks Who Deny HIV Link'
by David Perlman, 26 May 1994. No one was try-
ing to 'steal' anything. Furthermore, calling scientists
9 Kary Mullis deals with this quote in his CalijcJrnia Monthly
interview. What is a 'fact' for Baltimore (of Imanishi-Kari fame)
may not be a fact at all. One of the criteria of scientific standards
is the ability to tell the difference between a fact, an opinion, a
hypothesis, and a hole in the ground.
who raise questions and have gone through the proper
AAAS channels to organize their meeting 'rebels' doc-
uments how the S.F. Chronicle manipulates its readers.
Perlman's article started: 'Blindsided by a small band
of AIDS gadflies, America's largest scientific organiza-
tion moved yesterday to avoid sponsoring a one-sided
spate of oratory over the causes of the global AIDS
epidemic'. Among other things, Perlman reproduced
the criticism from Ascher and Winkelstein.
The AAAS symposium was subsequently covered
by Perlman in the San Francisco Chronicle. tO It also
received a 500 word notice 'Uncertain for sure' by
Susan Gerhard in the San Francisco Bay Guardian (6
July 1994, p. 32), which I found perceptive and sharp.
She had been alerted to the meeting via Celia Farber's
interview with Kary Mullis in SPIN. Gerhard wrote:
'While it may be OK for me and most of my friends to
believe in science - we have to, as we're not equipped
with our own labs and sets of petri dishes - we expect
more than blind devotion from the men and women of
Reason. It was truly frightening to watch how, with a
few pointed questions, they [the HIV critics, Duesberg
and Mullis in particular] made that religion - my reli-
gion for many of the last 10 years - look as arcane as
the Vatican's'. Gerhard concluded her piece with the
comment: 'The HIY critics didn't have answers; they
just had questions. But from the looks of this public
gathering, and the questions that cropped up from its
audience of laypeople and pros, their position of oppo-
sitional prying has been more welcome outside science
than within it'. Gerhard's article is one among other
pieces of evidence that the parallel local press (derived
from the counter-press of the sixties) is beginning to
warm up to the issue of HIV and the credibility of the
scientific establishment with respect to HIY.
Neither the NIDA meeting nor the AAAS meeting
were covered by Science and The New York Times.
If this surprises you, come to the front of the class
because you haven't been paying attention.
The AAAS symposium represented many views
about the relationship of HIY and AIDS, including
those who question the causality such as Duesberg and
Kary Mullis; the UC Berkeley Molecular Biologist
Harry Rubin, who is an agnostic as to the role of HIV
in causing AIDS; and supporters of the establishment
line, such as Jerold Lowenstein of the UC Medical
Center in San Francisco.
10 'AIDS Rebels Try to Steal Show', 26 Mayp. A14; 'AIDS Sym-
posiumChangesLine Up', 7 Junep. A15; 'S.F. Science Conference
to Debate Cause of AIDS', 18 June p. A6; 'Controversial AIDS
Theories Debated at Forum in S.F.', 22 June p. A7.

An extensive account of the AAAS symposium is
available on the electronic nets. The printout I was
given has about 30 pages, and includes an article by
John Lauritsen: 'Truth is Bustin' Out All Over: HIV
Symposium at AAAS Conference'. This account is
available from laurit@panix.com. It includes a more
detailed account of the pressures put on the AAAS to
cancel the symposium or to change its thrust, and it
includes extensive direct quotes from the participants.
Here is a sample quote from Kary Mullis, about the
(non)existence of a scientific reference giving evidence
whether HIV is the probable cause of AIDS:
I assumed there must be such a reference, and that
there might be a controversy over who got credit
for it, because I was under the impression that
Gallo and Montagnier might have been fighting
over who had first shown that HIV was the cause
of AIDS ... I went back over their early papers,
and found that neither of them had shown that HIV
was the probable cause of AIDS.
I was running into a lot of people who were
doing AIDS research, and every time somebody
would give a talk, I'd go up to them afterwards and
askpolite1y: Who I should quote-was there a paper
or a review that I should quote for that statement? It
seemed like a perfectly reasonable question to ask.
Some people took offence. Most people said the
same thing: 'But everybody knows, you don't have
to prove it'. Well, you know, everybody knows
the sequence [of a certain chemical], but they also
know where to find the references.
And I started getting uncomfortable with the
fact that nobody seemed to know. So I changed the
question to, 'When did you, personally, become
convinced that HIV is the probable cause of AIDS?
(I mean, you're working on it as though you are.)
[laughter] What papers did you read?' And they'd
say, 'I've got it in my office'. And I'd say, 'Would
you send me the titles, so I can look them up' ....
[They never did.]
The Lauritsen account on the e-nets reproduced a
telling exchange between Jerold Lowenstein and some
scientists questioning he role of HIV in causing AIDS.
Lowenstein's talk was entitled 'The medical and sci-
entific evidence for HIV being the cause of AIDS'.
Harvey Bialy raised a question:
BIALY. ... And finally, why are hemophiliacs not
dying of AIDS? They were all infected ten years
ago or more - way long enough to have exceed-
287
ed the latency period. Half the hemophiliacs in
the United States should be dead or dying of AIDS
now, and yet it's less than 12%. You need to explain
that. Please!
LOWENSTEIN. I don't see why I need to explain
that. Hemophiliacs are dying of AIDS.
BIALY. The HIV-AIDS hypothesis postulates a
ten-year latent period between infection and dis-
ease. That means that if you have 16 000 people
with the infection, after a ten-year period, approx-
imately half of them should have the disease. But
only 10-12% have the disease. This is a discrep-
ancy! How do you explain it?
LOWENSTEIN. How do you explain the 10-12%
who do die? [groans from the audience]
BIALY. What are they dying of? They're dying
of the same diseases that hemophiliacs always die
of, but now they're called 'AIDS' because they've
been diagnosed as having HIV-antibodies.
DUESBERG. Those hemophiliacs are not immor-
tal. [laughter]
BIALY. What is your evidence that HIV is destroy-
ing T-cells by infection? I would love to see it. I've
been waiting ten years for it.
[no response from Lowenstein]
Harry Rubin made several points, including some
technical points about retroviruses and some of the
history of these viruses associated with leukemia in
chickens. As he said (quotes taken from the Lauritsen
account on the e-nets):
Notice, I used the words, 'associated with'. They
were given the name Avian Leukosis Virus, indi-
cating they cause a type of leukemia in chickens,
along with many other symptoms, incidentally.
Now what I learned from my own work - I devel-
oped the way of assaying these viruses in culture
so they could be worked with, in a fairly expedient
manner - is that these leukemias could and would
occur in the absence of the retroviruses ....
Every cell in the chicken is infected, and
every cell is constantly producing virus, but even
then ... only 15% of those chickens, who were
congenitally infected, developed the leukosis. In
spite of these findings, these viruses are still called
Leukemia or Leukosis viruses, as they have been
for 85 years. The assumption is made that they are
the sole, or at least the prime, cause of the disease
in chickens ...
288
One of the things I want to point out is the
tricky business of naming a virus. Naming some-
thing HIV, Human Immunodeficiency Virus, Avian
Leukosis Virus, Avian Myelocytosis Virus - all of
those names fix in the minds of those who use them,
or work with them, that this is the proof.
Rubin also addressed the 'political problem':
What's transpired in the development of this sym-
posium is illustrative of the difficulty of making
a critical scientific analysis of the AIDS problem.
It's really more of a political than a scientific prob-
lem ...
Now I've come to my point about the politiciza-
tion of this issue. In 1988 the American Foundation
for AIDS Research (AmFAR) convened a meeting
in Washington, DC, which had the obvious purpose
of silencing Peter Duesberg. As I had discussed the
matter with Peter on many occasions, he asked me
to join the meeting, even though he knew I was an
agnostic about the role of HIV - more like Erasmus
than Martin Luther. I reluctantly agreed, feeling I
could play the role of an intermediary. How naive I
was! I did some extensive reading before the meet-
ing, and a lot of questions occurred in my mind,
that I thought needed discussion. When I raised
those questions at the meeting, I got the response
you might expect from a bunch of fundamental-
ists confronted with someone who questioned the
virgin birth. [laughter] For example, Anthony Fau-
ci interrupted me at one point, in a rage, saying
how could anyone doubt the compelling role of
HIV, when there was this HIV-infected baby, who
had never been exposed to other viruses, bacteria or
drugs, and developed AIDS. Well, I had no answer.
If I did, I couldn't get up, he was so made. Well,
I later learned that the mother of that baby was an
intravenous drug user who had all sorts of health
and nutritional problems ...
Rubin addressed the circularity of the definition of
AIDS:
Subsequently after that meeting, at a little social
gathering, I had a discussion with a medical corps
major (I won't mention any names) who was the
Army's leading AIDS specialist. He told me that
he had seen AIDS cases with Kaposi's sarcoma
in recruits, a condition then commonly associated
with AIDS, at least in homosexuals. He told me
that some of these cases were AIDS. And I asked
him if they differed clinically from the other six
cases [which were not AIDS]. He said no, they
didn't differ clinically at all, but they had antibod-
ies to HIV. So I realized then I was dealing with
a self-fulfilling prophecy. If there are HIV anti-
bodies when you have Kaposi's, then it's AIDS,
and if no antibodies when it's Kaposi's, then it's
not AIDS, just Kaposi's. No wonder there's such
a strong association between the virus and AIDS,
if the diagnosis is based on the presence of the
virus ...
Finally, Rubin brought up Duesberg:
In closing, let me say a word about Peter Dues-
berg, who has been pilloried from post to post in
the press, as you have seen. I made it clear that I do
not go along with his total rejection of a role for the
virus. I will say, that if it were not for Peter Dues-
berg, there would be no one raising questions at all,
including me. [applause for Duesberg] So while I
continue to disagree with him, and find him a pain
sometimes [laughter], I respect what he's done, and
I might say that he's done it at enormous sacrifice
to his reputation and to his career. [applause]
5. A press release on a 'Commentary' in Nature
A piece 'Does drug use cause AIDS?' by M.S. Ascher,
H.W. Sheppard, W. Winkelstein Jr. and E. Vittinghoff
was published in the Nature issue of 11 March 1993. 11
This piece was published as a 'Commentary'. About a
week before publication, Nature issued a press release
concerning this piece, headlined: 'DRUG USE DOES
NOT CAUSE AIDS'. The press release concluded:
'These findings seriously undermine the argument [sic]
put forward by Dr. Peter Duesberg, of the Universi-
ty of California at Berkeley, that drug consumption
causes AIDS, and instead provides [sic] strong sup-
port for the hypothesis that HIV causes the disease'.
Numerous members of the press started calling Dues-
berg to get his comments on the forthcoming article in
Nature, but the article had not been made available to
Duesberg. Despite the fact that the press release was
marked 'Embargoed for release 6:00 pm EST, Wednes-
II Nature identifies the authors as follows: Michael S. Ascher and
Haynes W. Sheppard are in the Viral and Rickettsial Disease Labora-
tory, California Department of Health Services, 2151 Berkeley Way,
Berkeley, CA 94704. Warren Winkelstein Jr. and Eric Vittinghoff
are in the Department of Biomedical and Environmental Health Sci-
ences, School of Public Health, University of California, Berkeley,
CA 94720.

day, March 10, 1993', Duesberg told me that on 4
March he got several calls from journalists, including
one from the New Scientist in Washington. Duesberg
told these journalists that he could not comment on a
piece he had not seen. The New Scientist then faxed
him a copy on 4 March. He received a copy from
Nature only on 9 March. Thus Nature and the authors
of the article use the media to manipulate public opin-
ion before their article had been submitted to scientific
scrutiny by other scientists (other than possible refer-
ees), and especially by Duesberg who is principally
concerned.
A misrepresentation in Nature's press release. Among
other things, Nature's press release misrepresented
how the sample of 1034 men for the purported study
was determined. The press release stated: 'These were
selected by random sampling of San Francisco house-
holds regardless of sexual preference, lifestyle, HIV
status or drug use'. But a qualification from the 'Com-
mentary' itself was left out in the press release. Indeed,
the 'Commentary' actually referred to a 'random sam-
pling from neighborhoods of San Francisco where the
AIDS epidemic had been most intense before 1984'.
Thus the press release suppressed the additional infor-
mation that the sampling came from a definite segment
of San Francisco households rather than random San
Francisco households.
The 'Commentary' further claimed: 'Participants
were recruited without regard to sexual preference,
lifestyle, or HIV serostatus (not known at the time),
and thus constitute a representative cross-section of
men in this community'. However, an area where the
'epidemic had been most intense' might already have a
preponderance of people in the major risk groups. This
was indeed the case. The sample had a built in selection
in the direction of 'sexual preference' and drug use. For
instance, about4/5thofthe 'random sample' classified
themselves as homosexual or bisexual.
As for HIV status and drug use, about 1/4th of the
'random sample' had AIDS-defining diseases (from
the CDC list). Because of the CDC circular defini-
tion, Ascher et al. identified 215 AIDS patients, and
reported that 100% of the AIDS patients were HIV
positive. However, an independent re-analysis of the
data brought to light another 45 patients with AIDS-
defining diseases, but HIV negative, and thus showed
that 83% of the patients with the AIDS defining dis-
eases were HIV positive. On the other hand, according
to a table in the Ascher et al. paper, 100% of the AIDS
patients had used recreational drugs including nitrites
289
(these patients fell into two categories, heavy use and
light use). The above mentioned re-analysis found that
all but three patients had reported the use of nitrites
and other recreational drugs, so nearly 100%. The oth-
er three were undetermined. Furthermore, 84% of the
HIV positives were also on AZT. Finally, homosexu-
als used twice as many recreational drugs as did the
heterosexuals (marijuana not included). 12
The independent re-analysis documented other
problems in the Ascher et at. 'Commentary', inval-
idating the statement made by Ascher et al. (p. 104,
column 2): 'However, the population-based SFMHS
provides a rigorously controlled epidemiological mod-
el for the evaluation of aetiological hypotheses'. For
instance: 'The Commentary, however, lacked the rigor
of a scientific paper. No detailed description of meth-
ods was given, numbers were 'adjusted' using unex-
plained techniques, and graphs were presented without
error bars, among other critical problems. Moreover,
the analysis itself suffered several fatal flaws, such as
using a circular HIV-based definition of AIDS, fail-
ing to quantify total drug use over time, and ignor-
ing drug-use-differences between HIV-positive and -
negative men'.
The article 'Debunking Doubts That HIV Caus-
es AIDS', by Gina Kolata in the New York Times
(11 March 1993, p. All) followed the Nature press
release in reporting incorrectly 'a group of 1034 ran-
domly selected single men who lived in San Francisco
and were 25 to 54 years old in 1984, when the study
began'. The New York Times also reported uncritical-
ly the misleading data from the Ascher et al. 'Com-
mentary'. Thus did the New York Times propagate the
misinformation of the press release and of the 'Com-
mentary'.
I take no position here on the relative merits of the
AIDS virus hypothesis or the AIDS drug hypothesis
(in whatever form they may be formulated). I do take a
position against the announcement of purported scien-
tific results via superficial and defective press releases,
and before scientists at large have had a chance to eval-
uate the scientific merits of such results and the data
on which such results are purportedly based.
Some other scientists reacted negati vel y to Nature's
publication. For example, Richard Strohman wrote a
letter to the editors of the San Francisco Chronicle,
12 See two articles: 'Can epidemiology detennine whether drugs
or HIV cause AIDS?', by Peter Duesberg, Aidsforschung vol. 12
(1993) pp. 627-635; and 'HIV as a surrogate marker for drug use:
A re-analysis of the San Francisco Men's Health Study' by Bryan J.
Ellison, Allen B. Downey, and Peter H. Duesberg, this volume.
290
which had rushed into print about the Nature article.
Strohman's letter was never printed, and I quote it in
full:
Letter to the editors of the San Francisco
Chronicle by Richard Strohman (sent 11 March
1993, never printed). I am dismayed by your treat-
ment of the AIDS-drug hypothesis (3/11/93). As
a piece of reporting it is a masterpiece of scien-
tific ignorance. First, in the article in question all
conclusions, dutifully reported by Mr. Perlman,
were drawn from hearsay. It is hearsay because
the article is not a scientific paper that survived
any rigorous review process; it was instead part
of what is called 'scientific correspondence' that
gets by with often cursory review by journal edi-
tors. Second, as a result of lack of thorough review
there is no detail given on methods used to col-
lect data. Third, without details on methods we can
not evaluate the data itself, never mind conclusions
drawn from that data. Thus, all standards of real
science are violated. What remains is only 'sci-
entific correspondence', at best a mechanism for
developing opinion or debate. In the mainstream
of science or in a court of law it would be thrown
out as hearsay evidence. Instead of asking why the
authors of this very 'important' study did not take
the trouble to submit their work through normal
channels, but instead chose the less rigorous pro-
cess, the Chronicle chooses to treat the work as
valid, proven, information. The Chronicle owes all
its readers, and especially all HIV+ people a pro-
found apology.
The authors of the 'Commentary' in Nature ended
their piece as follows:
The energies of Duesberg and his followers could
better be applied to unravelling the enigmatic
mechanism of the HIV pathogenesis of AIDS.
To this end, we have proposed an alternative
model 14 ,lS based on HIV signalling at CD4 cells.
This model and others are now being evaluated,
and we cordially invite Duesberg to participate in
this endeavour. [I omit the footnotes 14 and 15.]
I find it presumptuous and objectionable for sci-
entists to tell others where energies 'could better be
applied'. Scientific standards as I have known them
since I was a freshman at Caltech require that some
energies be applied to scrutinize data on which exper-
iments are based, in documenting the accuracy of the
data, its significance, its completeness, and to deter-
mine whether conclusions allegedly based on these
data are legitimate or not.
Especially in connection with the last para-
graph telling scientists where to apply their energies,
Strohman also wrote an open letter to Warren Winkel-
stein, one of the authors and a colleague at DC Berkeley
(The Daily Californian, 1 April 1993).
Extract from Strohman's open letter to Winkel-
stein. Dear Warren, The HIV-AIDS hypothesis is
a crucial problem that must be either discarded or
proven. We all agree to that. As stated in your recent
Nature article, scientists stilI do not know how
HIV works, and until that time we must all strive
to do what we can to find a solution. Your own
work has striven to develop a strong correlation
between HIV and AIDS, but you agree that corre-
lation does not establish cause. More than 90% of a
multibillion dollar budget is dedicated to finding a
molecular link between the virus and immunosup-
pression, with stilI no definitive proof after more
than 10 years. Meanwhile, there are some scien-
tists, myself included, calling for approaches to
AIDS other than the near-monolithic HIV theo-
ry. Perhaps other factors are involved; goodness
knows, there certainly is convincing evidence for
co-factors, and for Peter Duesberg's theory that
AIDS is caused by drugs alone. The drugs he men-
tions most often are recreational drugs taken by
some, but not all, gay men, and intravenous drug
addicts. In addition, AZT, which is prescribed to
deal with bacterial and viral infections, is known
to be cytotoxic to human cells, and in itself could
be the culprit.
My question, really for all of us, is the fol-
lowing. Why is it necessary to insistently call on
dissenters from the mainstream theory to aban-
don their dissent and to join ranks with those who
believe that HIV, and only HIV, causes AIDS? You
yourself issue such a call in your recent Nature
article (as quoted now in newspapers all over the
country; SF Chronicle of 3/11/93). This is not how
science is supposed to operate. It is supposed to
be pluralistic; it is historically best when dissent is
open and wide; results come more quickly when
support is given not only to those who follow the
major paradigm, but also to those who have rea-
soned the unpopular approaches ...

Winkelstein answered Strohman's letter in The Dai-
ly Cal of 13 April, 1993, stating in part:
Extract from Winkelstein's answer to Strohman.
Your assertions regarding alternative approaches
and dissenting opinions is best answered by quot-
ing what we actually wrote in the Nature commen-
tary: 'The main purpose of the cohort studies con-
ducted in San Francisco and elsewhere has been to
look for associations of environmental or behav-
ioral factors with the development of AIDS. Had
any factor other than HIV infections been found, it
would have been reported immediatel y ... ' [elision
by the Daily Californian. In his reply, Winkelstein
also repeated the paragraph I have quotedfrom his
article, about where the energies of Duesberg and
his followers could better be spent. He then added
the following:]
In a New York Times article reporting the con-
tent of our Nature commentary, Dr. Jerome Groop-
man, a distinguished medical scientist, is quoted as
follows: 'Science keeps an open mind at all times,
but there comes a time when you have to declare
that the earth is not flat. It is incumbent on those
who reject HIV to come to terms with this'.
Thus Winkelstein and the 'distinguished medical
scientist' Groopman equate those who question the
HIV hypothesis with f1at-earthers. I ask readers to eval-
uate Winkelstein's scientific standards in light of:
- the criticisms to which the 'Commentary' with
Winkelstein as co-author was subjected in the arti-
cle 'HIV as a surrogate marker for drug use. A re-
analysis of the San Francisco Man's Health Study'
(see footnote 12);
- the challenges to the HIV-AIDS hypothesis by a
number of scientists, including those mentioned in
this article;
- the questions which have been raised at the AAAS
and NIDA meetings concerning drug use as a pos-
sible cause of some AIDS-defining diseases.
The above-mentioned article critical of the Ascher
et al. 'Commentary' was submitted for publication in
Nature, but rejected. As we have already mentioned,
Nature's editor John Maddox expressed his position
clearly about the refusal to publish: ' ... the right
of reply has to be modulated by its content'. (Nature
291
363, 13 May 1993, p. 109.)13 Neville Hodgkinson
reported Nature's refusal to publish these criticisms of
the Ascher et al. paper in the London Sunday Times (l
May 1994), under the title: 'Poppers and Propaganda-
Censorship is blocking the debate vital to discovering
the truth about AIDS'. He wrote that
repeated efforts by Duesberg and others to reply
to the attacks on him have been frustrated by John
Maddox, the journal's editor. Their latest effort, re-
analyzing data from an eight-year study of homo-
sexual men in San Francisco, was rejected two
weeks ago. It reaches conclusions that directly con-
tradict those in the original article. Almost 100% of
the men who died had used poppers, and there was
a much higher level of general drug use (includ-
ing heroin and cocaine) among HIV-positive men
than their HIV-negative counterparts ... To refuse
Duesberg and colleagues any right of reply is an
act of censorship on one of the most important sci-
entific debates of our time.
Hodgkinson also gave the more general evaluation:
A kind of collective insanity over HIV and AIDS
has gripped leaders of the scientific and medical
profession. They have stopped behaving as sci-
entists, and instead are working as propagandists,
trying desperately to keep alive a failed theory.
Thus the scientific community, and especially the lead-
ers of science, have exposed themselves to a loss of
trust in the community at large.
Update, 5 January 1995
6. An article in Science, 9 December 1994
On 9 December, 1994, Science published an 8-page
analysis of some dissent concerning HIV as a cause
13 Maddox also claims it is Nature's responsibility to 'censor'
information. An interview with Der Spiegel (45/1994, p. 229), head-
ed 'Filtern und zensieren' - Interview mit John Maddox tiber die
Rolle seiner Zeitschrift Nature. contains the following exchange:
DER SPIEGEL. Wissenschaftler werfen Ihnen vor, Nature tibe
mit seinem Gutachtersystem zuviel Macht aus. Die Informationen
wtirden gefiltert .. .
MADDOX . . . . sogar zensiert: Wir haben uns zum Beispiel
geweigert, die These von Peter Duesberg zu verOffentlichen, nicht
HIV, sondern Drogenkonsumsei die Ursache von Aids.
292
of AIDS (pp. 1642-1649). The article in several parts,
authored by Jon Cohen, was headlined:
The Duesberg Phenomenon
A Berkeley virologist and his supporters continue
to argue that HIV is not the cause of AIDS
A 3-month investigation by Science evaluates their
claims
Science (and not just its reporter Jon Cohen) took
responsibility for the investigation and its conclusions.
Aside from the displayed responsibility of 'a 3-month
investigation by Science' in the heading, responsibility
was further taken on the very first page, where Science
was mentioned three more times as follows:
But because the Duesberg phenomenon has not
gone away and may be growing, Science decided
this was a good time to examine Duesberg's main
claims. In a 3-month investigation, Science inter-
viewed more than 50 supporters and detractors ...
The main conclusions of Science's investigation
are that:
- In hemophiliacs ... there is abundant evidence
that HIV causes disease and death (see p. 1645).
- According to some AIDS researchers, HIV now
fulfills the classic postulates of disease causation
established by Robert Koch (see p. 1647).
- The AIDS epidemic in Thailand, which Duesberg
has cited as confirmation of his theories, seems
instead to confirm the role of HIV (see p. 1647).
- AZT and illicit drugs, which Duesberg argues
can cause AIDS, don't cause the immune deficien-
cy characteristic of that disease (p. 1648).
I regard the Science article of 9 December 1994, as
tendentious and skewed, but here is not the place to
make a comprehensive detailed analysis. However, I
give a couple of examples.
First I object to personalizing dissent about the
official line that 'HIV causes AIDS' in the context
of 'The Duesberg Phenomenon'. I object to lumping
together different people such as Harry Haverkos (who
sponsored the NIDA May 1994 meeting on nitrite
inhalants), the co-authors of the article on AIDS in
Africa14 referred to in footnote 4, or myself among
14 These co-authors include especially Harvey Bialy, research edi-
tor of Biotechnology. Cohen tried to interview me. I asked that his
questions be put in writing, and he faxed me a letter containing
many others (for instance the Group for the Scientif-
ic Reappraisal of the HIV/AIDS Hypothesis), as part
of 'the Duesberg phenomenon'. What has 'not gone
away' is that an increasing number of individual sci-
entists, with different points of view, different back-
grounds, and different responsibilities, have publicly
documented reservations about the official position of
the government or the scientific establishment con-
cerning HIV and AIDS. Lumping together indepen-
dent scientists under the single category of Duesberg
'supporters' skewed the perspective on the dissenters
and on their multiple reasons for dissent.
Second, the article completely omitted mention of
dissenters such as Bialy and Haverkos, as well as many
points raised by the dissenters. For example, the NIDA
meeting of May, the position of Harry Haverkos on
nitrite inhalants, the situation in Africa, the fact that
malaria, tuberculosis, leprosy, and influenza, test false
positive on the HIV antibodies test, were still not men-
tioned in the Science article. The AAAS June meeting
was mentioned in only one sentence: 'In June, the
Pacific Division of the American Association for the
Advancement of Science (publisher of Science) spon-
sored a day long meeting at which the dissidents offered
their points of view'. No indication was given what
these points of view were.
questions on I November 1994. I found Cohen's questions and
statements so defective that I refused to deal with him, and wrote
a letter to Koshland explaining in detail why I refused to deal with
Cohen. I made a line by line analysis of Cohen's letter to me. For
example, Cohen wrote me: 'You extensively cite Duesberg's writ-
ings and references that he has provided you with, yet I do not see
any other references of AIDS literature. Have you investigated the
AIDS literature to address the question about the link between HlV
and AIDS?'
Cohen was referring to the present article, which I had sent to him
before publication in the Yale Scientific. As I wrote to Koshland,
Cohen's statement (,Yet I do not see .. ') documents blindness, as
well as incompetence in processing information. To cite just two
examples, in my article I quote from a paper by Papadopoulos et
at. (especially Bialy), and I devote an entire section to the paper by
Ascher et al., published by Nature, and reported in the New }{Jrk
Times among many other newspapers which took seriously a press
release by Nature. I did not get either of these papers from Duesberg.
Bialy himself sent me his preprint.
In any case, what of it if Duesberg is kind enough to provide me
with scholarly references at my request? I learned that malaria tests
false positive for HIV antibodies from the Kary Mullis interview
in the Cal!fiJrnia Monthly, and I learned of a similar situation with
respect to leprosy and tuberculosis from Neville Hodgkinson in the
London Sunday Times. I asked Duesberg to provide me with the
scholarly references to that effect, and he brought to my attention
the actual scientific papers by others, reporting these facts. Scien-
tifically, it does not matter who provided me with these references
or when, but it was appropriate to acknowledge Duesberg for his
bibliographical help.

Especially significantly, as we shall see below, the
9 December 1994 article also made no mention of
Kaposi's sarcoma.
7. Other viruses and reports in the press
No hypothesis can be dismissed a priori. It is still a pos-
sibility that some virus(es) other than HIV sometimes
cause some of the diseases listed under the 'AIDS'
umbrella by the CDC. We have already mentioned
the possibility that different diseases in different risk
groups may have different causes. The medical liter-
ature has a number of papers raising questions about
many viruses, whether they are harmful or not, and
how. Here I shall mention two of them.
HHV-6. One candidate has been the Human Herpes
Virus 6, abbreviated HHV 6, as in the article 'Human
Herpesvirus 6 in lung tissue from patients with pneu-
monitis after bone marrow transplantation' (New Eng-
land J. of Medicine 329, 15 July 1993, pp. 156-161).
However, the article starts: 'Human herpesvirus 6
(HHV6) infects over 90 percent of the U.S. population
early in life, causing fever or rash in some children'.
To what extent does it make sense that such a common
virus is 'the' or 'a' cause of some ofthe AIDS-defining
diseases and under what circumstances? The above
article itself is cautious in the summary conclusion
at the beginning, where it states: 'The concentrations
of HHV-6 genomes in lung tissue and their relation
to changes in serologic titers support an association
between HHV-6 infection and isopathic pneumonitis
in immunocompromised hosts'. Here we meet typical
examples of arising questions: whether there is merely
an 'association' between a virus and some diseases, or
whether a virus is a cause, and if so how. It is then
a problem to make experiments to determine whether
a given virus is merely a passenger virus, whether it
lies dormant, and if it is awakened (how?) whether it
merely shows its presence by testing positive in various
ways (antibodies?), or whether it is or becomes harm-
ful (how?), under certain circumstances (which?).
Still another virus. On 16 December 1994, Science
published a technical paper suggesting that a new virus
may cause Kaposi's sarcoma. IS News articles on this
15 Y. Chang et al., 'Identification of Herpesvirus-Like DNA
Sequences in AIDS-Associated Kaposi's Sarcoma', Science (16
December 1994) pp. 1865-1869.
293
paper occurred on that same day both in the New York
Times and in Science as we shall now describe.
The New York Times (16 December, 1994, p. 1). For
the first time to my knowledge an article by Lawrence
K. Altman mentioned another virus besides HIV as
a possible cause for 'AIDS' under the title: 'Appar-
ent Virus May Be a Cause Of Fatal Cancer in AIDS
Patients'. A salient fact is that HIV is nowhere men-
tioned in the article. A paragraph describing a certain
phenomenon concerning the distribution of Kaposi's
sarcoma among 'people with AIDS ... gay and bisex-
ual men ... and women with AIDS', is followed by the
sentences: 'Experts say the introduction of a previous-
ly unknown virus that coincided with the advent of the
epidemic of AIDS could explain such a phenomenon.
Although a number of efforts have been made to link
known infectious agents with Kaposi's sarcoma, none
have held up'.
Words in the headline such as 'apparent' and 'may
be' were fully appropriate to the subsequent write up.
Altman stated: 'Scientists at Columbia University said
they had found strong evidence of an apparent newly
detected virus that, they said, might cause Kaposi's
sarcoma in people with AIDS. Kaposi's is the most
common cancer affecting gay men with AIDS, and
one of the principle [sic] causes of death among that
group'.
Science (16 December 1994, p. 1803). Jon Cohen
wrote the Science 'Research News' article headlined:
Is a New Virus the Cause of KS? Kaposi's sarcoma,
a once-rare skin tumor, is a scourge of gay men with
AIDS. Several theories have attempted to explain it.
The latest: a novel herpesvirus
Cohen quoted one of the co-authors of the scientific
paper, Patrick Moore, as saying that 'this virus is prob-
ably playing a central role'. Cohen then added: 'That
thesis will be intensely scrutinized over the coming
months. But if it stands up, solid headway will have
been made toward solving a vexing riddle that arose
more than a decade ago when an old tumor began pop-
ping up in new places, with deadly results'.
These Science and New York Times articles are
questionable on several grounds.
(a) What is 'AIDS'? No definition of 'AIDS' was giv-
294
en in either article. We have seen that KS is listed
among the 29 diseases which define AIDS in the pres-
ence of HIV according to the CDC (see footnote 1).
Expressions such as 'Kaposi's sarcoma in people with
AIDS' (New York Times), and 'Kaposi's sarcoma ... is
a scourge in gay men with AIDS' (Science), repre-
sent shifting terminology, compounding the confusion
about HIV and AIDS, and possibly representing the
beginning of a rewriting of history concerning 'AIDS'
and what it means.
(b) What virus? Furthermore, no virus had been found.
TheNew York Times article subsequently stated that the
scientists found sequences of DNA which an 'expert
in herpes viruses at Yale University' said were 'con-
sistent with a new herpes virus'. But the 'expert' who
said that also cautioned: 'There is a long step between
finding DNA sequences and having a virus'.
(c) What cause? There is also a long step between
finding yet another latent virus and showing that it
causes various forms of cancer, especially while it
is dormant. The Times article contained one sentence
to the effect that 'even if the virus turns out to be
a previously unknown one, they said, much research
needed to be done to prove that it was the cause of
Kaposi's sarcoma. The possibility exists that the virus
is present in Kaposi's sarcoma only after the cancer
develops'. According to Duesberg, the fact that the
DNA sequences were discovered only by amplifica-
tion via PCR indicates that whatever is there, virus or
not, is inactive and sparse. Duesberg added that there
is no precedent for a virus causing cancer or another
fatal disease while it is latent.
Harold Jaffe was quoted in the New York Times as say-
ing: 'It's a strong candidate to be the Kaposi sarcoma
agent'. So Jaffe was up to his usual rhetoric, since first,
there is no candidate yet, and second the definite arti-
cle ('the' Kaposi sarcoma agent) is unwarranted since
Kaposi's sarcoma could be caused by several differ-
ent agents, depending on the time, place, risk groups,
various practices, or whatever, as I have repeatedly
emphasized. Jaffe was similarly quoted in Science: 'I
think it's a tremendously exciting result. At this point,
we can't say it's the etiologic agent, but I think it's a
very good candidate' .
So the New York Times and Science articles are
worth mentioning here as important examples of
the ongoing problematic and questionable journalis-
tic treatment of HIV and AIDS (whatever AIDS is),
as well as examples of the fixation by some scientists,
the New York Times and Science on the finding of a
virus, without bringing up other possibilities (e.g. tox-
ic agents such as drugs).
(d) Joining the dissenters. Nevertheless, by bringing
up a new virus as a possible cause of KS, and by the
evaluation 'solid headway' concerning possible devel-
opments about such a 'new virus', Altman and Cohen
became HIV dissidents. Since KS is a hallmark of
'AIDS' according to the CDC definition, it follows
that Lawrence K. Altman, Jon Cohen, and the scien-
tists whom they quoted as proposing a 'new virus' to
be the cause of KS, joined those who dissent from
the unqualified view that 'HIV is the virus that causes
AIDS'.
Update July 1995, in proofs
A further article by Jon Cohen titled 'Controversy:
Is KS Really Caused By New Herpesvirus?' (Science
268,30 June 1995, pp. 1847-1848) continued spread-
ing the unreliable mess coming from Science and var-
ious scientists. The article to a large extent nullified
the hype in the 16 December 1994 article, by report-
ing 'deep reservations' about the role of the Herpes
virus as a cause of KS, and also reporting that 'those
misgivings had been muted - until the AIDS-KS meet-
ing' sponsored by the National Cancer Institute, 5 and 6
June 1995 in Bethesda MD. Cohen reported that' Gallo
was at the center of the debate' and that 'Gallo's with-
ering critique of KSHV packed a punch'. Oncologist
Parkash Gill of the University of Southern California
is reported as saying that 'she has failed to find DNA
sequences from KSHV in 11 KS cell lines' , and Cohen
quoted here: 'I think the interpretation has gone beyond
the data' . Cohen also wrote: 'Other researchers such as
NCI epidemiologist Robert Biggar, were enthusiastic
about the early evidence but now have doubts about
the virus'. On the other hand: 'Columbia University'S
Chang stuck by the data she and others have amassed
that supports KSHV's role in KS'.
Rep. Gil Gutknecht (R-MN) had raised questions
about HIV, AIDS and Kaposi's Sarcoma in a letter dat-
ed 24 March 1995 and addressed to Anthony Fauci,
with copies to several government officials and sci-
entists in HHS, NIH and CDC. HHS Secretary Don-
na Shalala responded in a letter dated 10 July 1995.
The response was seriously defective, partly because
she repeatedly made undocumented ex cathedra asser-
 295

tions. For example, in that response, it was asserted

among other things: 'The cause of Kaposi's Sarcoma
appears to be a newly discovered Herpes-like virus; .. ' .
Shalala gave no reference for this assertion. As we ana-
lyzed previously, the Science 16 December 1994 article
on the role of a Herpesvirus already contained some
cautious evaluations, mixed with some hype. Shalala's
answer reflects only the hype, and takes no account
of the subsequent article of 30 June 1995 reporting
on the 'controversy'. Her answer, occurring almost at
the same time as the 'deep reservations ... misgiv-
ings ... withering critique of KSHV .. .', provides a
typical example of the misinformation, contradictions,
and unreliable mess which arise from officials in HHS
or NIH concerning HIV and AIDS. Caveat emptor.

WHAT THEY SAID In addition, those favoring a more direct role of

At a meeting sponsored by the National Institute on
Drug Abuse (NIDA) on the toxic effects of nitrite
inhalants, 23 and 24 May 1994, Rockville MD:
... according to Jay Paul of the University of California
at San Francisco, the highest risk for AIDS invol ves the
use of poppers and four other drugs. And Lisa Jacob-
son of Johns Hopkins University (Baltimore, MD)
reported that 60-70 percent of the several thousand
gay men at risk for AIDS who participate in the Multi-
center AIDS Cohort Study (MACS) have used nitrites.
nitrites in AIDS pointed to data from the MACS show-
ing that HIV-negatives had, on average, 25 months
of nitrite use, HIV-positives had 60 months of nitrite
use, and AIDS patients had over 65 months of nitrite
use - an apparent dose-response relation. When asked
whether there was even one gay AIDS case in the
cohort who had not used drugs, a somewhat-surprised
Jacobson replied, 'I have never looked at the data in
this way'.
[Reported in the article 'NIH reconsiders nitrites'
link to AIDS' by John Lauritsen, Biotechnology, 12
Aug ust 1994.]
 P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 297-307, 1996.
© 1996 Kluwer Academic Publishers.
To fund or not to fund, that is the question: proposed experiments on the
drug-AIDS hypothesis
To inform or not to inform, that is another question*
Serge Lang
Yale University, New Haven, CT, USA
Since Gallo's press conference with HHS Secretary
Margaret Heckler in 1984, the HIV-AIDS hypothesis
that 'HIV is the virus that causes AIDS' has generally
been accepted. Some people, notably Peter Duesberg,
have pointed to serious difficulties about the scientific
basis for this hypothesis, and have proposed anoth-
er hypothesis, the drug hypothesis, that under certain
conditions, involving the quantity and nature of drugs
taken over certain periods of time, drug use may be
a cause of certain diseases which have been listed by
the CDC as AIDS related diseases. I take no posi-
tion at this time concerning the validity of any of these
hypotheses, but I am concerned here with the history of
a proposal by Duesberg to perform some experiments
to test the drug hypothesis. The bottom line is that
the NIH Center for Drug Abuse refused the funding,
and the matter was not reported in the scientific press,
notably Science, at the time, thus raising two issues:
one about the legitimacy of refusing such funding, and
the other about the way the scientific community is
not informed properly of some events which some sci-
entists regard as important. The'documentation I shall
provide can also be used to evaluate the verdicts of sci-
entific reviewers concerning the funding of a proposal
that goes against accepted ideas.
1. The proposal
Duesberg filed a grant application to the HHS Public
Health Service on 30 August 1993. The purpose of the
application was to examine the effect of some drugs
(nitrites) on some animals to see if they cause AIDS-
related diseases involving both immunodeficiency and
• Reprinted from the Yale Scientific, winter 1994-1995, updated
5 January 1995.
297
cancer type diseases. As Duesberg once said, 'we'll
feed poppers to mice' . Duesberg filled in the box asking
for 'the application's broad, long-term objects, mak-
ing specific reference to the health-relatedness of the
project' in more standard scientific language, as fol-
lows:
From Duesberg 's funding application
The long-term consumption of nitrite inhalants
has been suggested since 1981 as a possible con-
tributing factor to AIDS. Epidemiological correla-
tions have established a dose-response relationship
between nitrite consumption and AIDS risk, and
the restriction in their use to the active homosex-
ual community correlates well with the restriction
of Kaposi's sarcoma in homosexuals with AIDS.
Long-term exposure of mice to nitrites can result in
immune suppression. However, such toxicological
experiments have thus far remained inconclusive,
because they have not been carried out at an ade-
quate dose and length of time.
Following and exceeding unfinished studies by
others from the mid-1980s, it is proposed here to
determine the effects of the long-term inhalation of
nitrites on mice (e.g. 6 h per day, 5 days per week,
for 6 to 24 months). To distinguish between the
roles of nitrites as autonomous pathogens and as
co-factors of HIV, murine retrovirus-infected and
un-infected mice will be studied in parallel. The
parameters to be monitored include a) weight loss,
b) anaemia and lymphocytopenia, c) clinical mani-
festations of immunodeficiency, particularly Pneu-
mocystis pneumonia, d) evidence for Kaposi's sar-
coma. In addition, we propose to study the effects
of nitrites on the growth ratenf human t-celllines
298
in culture. Finally we plan to examine the Kaposi
sarcomagenic potential of nitrites on rodent cells
in culture. Avoiding the toxicity to vital organs,
like the lung and the bone marrow, the cell culture
system will permit us to test nitrites at higher-than-
in-vivo concentrations. This is critical to detect
sarcomagenic potential, because Kaposi sarcomas
are typically restricted to humans with the highest
cumulative lifetime doses of nitrites.
The proposed research would clarify whether
immunosuppression and/or Kaposi sarcoma can
result from long-term exposure to nitrite inhalants.
Public health efforts aimed at AIDS prevention
might increase their effectiveness by discouraging
the recreational use of nitrites and other psychoac-
tive drugs, thereby lowering the AIDS risk even of
those already infected by HIY.
It is not generally realized that the nitrites-AIDS
hypothesis (that nitrites playa strong role in causing
AIDS) was the first one offered by scientists, dating
back to around 1980. 1
1 According to Haverkos (1988), p. 165: 'Nitrite inhalants were
investigated as a possible cause of AIDS early in the epidemic, partly
because of the preponderance of homosexual men who used nitrites
among the early patients with AIDS ... '
'In 1981, CDC initiated surveillance in the United States for
patients under age 60 with KS and opportunistic infections ... The
initial CDC definition of AIDS did not require immunologic studies
or testing for any possible viral causes, nor did it exclude patients
with normal immunologic results (34), .
Some experiments were made at that time, and were mentioned in
a report on AIDS by the Centers for Disease Control (CDC, 1983)
(p. 44). The CDC concluded that 'although the data obtained in this
study indicate that IBN was not immunotoxic for mice, these drugs
do have toxic effects ... Reported side effects include: dizziness,
headache, tachycardia, syncope, hypotension, and increased intraoc-
ular pressure ... Nitrite inhalants do not appear to be implicated as
a cause of the immunosuppression seen in AIDS, but their role as
a cofactor in some of the illnesses found in this syndrome has not
been ruled out'. One effect of the CDC taking this position was to
influence others not to do further experiments in the direction of the
nitrites-AIDS hypothesis.
In 1985, according to that same article by Haverkos: 'Following
the identification of human immunodeficiency virus (HIV) as the
cause of AIDS, CDC changed the definition of AIDS to include HIV
serology testing as part of the definition ... ' (CDC, 1985).
The book AIDS - The Making ofa Chronic Disease (Fee & Fox,
1990) contains an article by Gerald Oppenheimer, giving a history of
the early days when the nitrite-AIDS hypothesis was considered seri-
ously, and studies were made on groups of homosexual or bisexual
men, who were found to use drugs, especially nitrites, extensively
(see especially pp. 57-60). Later in his article, Oppenheimerconsid-
ers the history of the HIV-AIDS hypothesis, and concludes (p. 75):
'The history of the epidemic demonstrates that the construction of
HIV infection was and is a dynamic process in which different sci-
Duesberg's grant application was made to the
proper agency, the National Institute on Drug Abuse
(NIDA), whose responsibility it is to fund such exper-
iments as he proposed, and which has funded such
experiments in the past. In 1988 NIDA even pub-
lished a monograph entitled 'Health hazards of nitrite
inhalants' (Haverkos & Dougherty, 1988). This mono-
graph dealt with many aspects of toxicity of nitrite
inhalants. 2 Among other things it described the strong
epidemiological and clinical evidence, as well as
experimental evidence resulting from experiments on
mice. The evidence from these experiments support-
ed the nitrite-AIDS hypothesis. The NIDA monograph
shows that as late as 1988, research into the nitrites-
AIDS hypothesis was regarded by some people in the
NIDA as a legitimate field of scientific inquiry.
According to Duesberg, his proposal was original-
ly solicited by the above monograph's co-editor (and
author of one of the articles in the monograph) Harry
Haverkos, clinical director of AIDS research at NIDA.
Thus Haverkos found it appropriate to NIDA's mis-
sion, and according to Duesberg, Haverkos consid-
ers if unfortunate that no testing of the nitrite-AIDS
hypothesis is currently being performed, because he
and other toxicologists agree that much evidence indi-
cates an important role for nitrites in AIDS. The pref-
ace to the monograph by Haverkos and his co-editor is
compatible with this view.
The reviewers of Duesberg's proposal for NIDA
wrote a specific positive recognition in connection with
the proposal. They asserted (p. 2 of the review): 'The
major strength of this proposal is that it addresses the
important public health problems of whether nitrite
abuse acts as a cofactor in AIDS pathogenesis and if
nitrites can cause Kaposi's sarcoma in the absence of
retrovirus infection' .
The NIDA reviewers also explicitly recognized the
credentials of the applicants. The proposal involved
a collaboration between Duesberg, whose expertise
entific specialties negotiated definitions that, to a degree, reflected
their relative power'.
2 Titles of the sections: Nitrite inhalants: Historical Perspec-
tive; The Fate and Toxicity of Butyl Nitrites; The Acute Toxicity
of Nitrite Inhalants; Indications From Animal and Chemical Experi-
ments of a Carcinogenic Role for Isobutyl Nitrite; Toxicity ofinhaled
Isobutyl Nitrite in Balb/c Mice: Systemic and Immunotoxic Stud-
ies; Altered T-Cell Helper/Suppressor Ratio in Mice Chronically
Exposed to Amyl Nitrite; Effects of Nitrites on the Immune Sys-
tem of Humans; Deliberate Inhalation of Isobutyl Nitrite During
Adolescence: A Descriptive Study; Nitrite Inhalants: Contemporary
Patterns of Abuse; Epidemiologic Studies - Kaposi's Sarcoma Vs.
Opportunistic Infections Among Homosexual Men With AIDS.

lies in chemistry and retroviruses, and Otto Raabe, an
inhalation toxicologist. The above evaluation of 'the
major strength' of the proposal was followed by an
evaluation of the investigators: 'In addition, the pro-
posed investigative team has expertise in retrovirus
research, inhalation research, and immune cell culture
and has the potential to carry out collaborative research
in this area'. The NIDA reviewers followed up with a
similar statement on p. 4. However, after recogniz-
ing explicitly 'the potential to carry out collaborative
research in this area' , the reviewers made the apparent-
1y contradictory statement: 'However, the lack of direct
experience of any of the researchers with nitrite studies
and the lack of publications dealing with nitrites does
detract from the likelihood of success of the proposed
project' . We shall deal with this reservation and others
in the next section.
Duesberg's application was supported, among oth-
ers, by Science editor Daniel E. Koshland, who wrote
directly to the Study Section of the National Institute
on Drug Abuse on 26 August, 1993. Koshland stat-
ed: 'As an observer, I have in the past been critical
of Duesberg for not suggesting experiments to resolve
this controversy. However, he has now answered my
call with a proposal to test the role of nitrite inhalants
as a cofactor in AIDS. Certainly this idea seems intu-
itively to have merit, as nitrites have long been known
for their proven mutagenic and carcinogenic effects.
He plans to extend some unfinished work by other
laboratories in the mid-1980s on mice, examining the
physiological and immunological effects of long-term
(six months or more) exposure to volatile nitrites'.
Koshland added that 'while the early research
yielded promising results, including evidence of
immunotoxicity, it was never properly confirmed or
followed up. Duesberg's proposal is a specific, work-
able one that will be done in collaboration with an
inhalation toxicologist at the University of California,
Davis'. Koshland also commented more generally that
'given the critical information that would be generated
by such a study, regardless of its outcome, I believe the
time has come for this experiment to be performed'.
2. Non-funding of the Duesberg-Raabe
proposal
In December 1993, Duesberg received notice that his
application would not be funded. The boxed official
statement to this effect was:
299
The scientific merit review of your application
(IROloAlAIOa3391-01) is complete. The Initial
Review Group (IRG) has recommended that NO
FURTHER CONSIDERATION BE GIVEN TO
THIS APPLICATION. Applications so designated
cannot be funded in their current form; therefore,
they are not routinely scheduled for second level
review by the National Advisory CouncillBoard.
An IRG summary statement containing important
evaluative comments will automatically be sent
to you in approximately 8 weeks. Until then, no
specific information regarding the review will be
available. However, you may call the contact num-
ber above at any time with other questions. After
receiving your summary statement you may also
call to discuss the contents, and for advice regard-
ing a possible resubmission. If you submit a revised
application, you must follow the instructions in the
application form and respond especially to com-
ments in the summary statement.
Thus the proposal did not even receive a 'priority
score', or a full review, but was summarily rejected at
the initial stage.
The 'Summary Statement' rejecting the proposal
contained several objections:
One objection was that 'the proposal does not
describe any preliminary studies', although the Sum-
mary Statement recognized that 'the preliminary stud-
ies section describes experiments performed by other
groups that should be in the background and signif-
icance section'. Indeed, the proposal described sys-
tematically many preliminary studies by other groups.
Why it should be a cause for rejection that Duesberg's
lab did not do preliminary studies when others have
done them is beyond me, and I regard this reason as
illegitimate. It is now for the community of scientists
to evaluate the legitimacy of this reason. Aside from
that, the Duesberg lab does not have the money to make
preliminary studies, so it's caught in a Catch 22 situa-
tion even if one accepts (which I do not) the legitimacy
ofthe objection (universally? in some specific case? in
the presence case?).
Another objection is that some studies indicate that
certain concentrations of amyl nitrite proposed in the
Duesberg proposal are too low to cause immunodefi-
ciency in mice, and thus 'may not produce meaningful
results since this dose was not immunotoxic in several
studies'. However, the proposal did propose to vary
the concentration of amyl nitrite, starting with low
doses and increasing the doses in an attempt to deter-
300
mine thresholds of toxicity, so the objection is simply
invalid.
A third objection was that only a 'onesided ratio-
nale' was presented for the proposal. 'A more thor-
ough and balanced description of the pertinent litera-
ture would instill more confidence in the rationale and
design of the proposed studies'. I regard this objection
as invalid. The proposal took place in a well-known
history of AIDS when others, including those who con-
tributed to NIDA's research monograph 'Health Haz-
ards of Nitrite Inhalants' , had found results compatible
with or even supporting the nitrite-AIDS hypothesis.
Such results need to be complemented by further exper-
iments instead of being discouraged. It was not Dues-
berg's responsibility to present a many-sided rationale
for doing the proposed experiment. The experiment
was designed for a specific purpose, and would add
knowledge complementary to other available results.
Let the experiment be done, and we'll see what comes
out.
It was claimed that 'the proposed design of the
mouse experiments is not clear', because of the order
in which inhalants would be given after exposure of
the mice to virus. But the proposal would give mice
virus and inhalants simultaneously, and see how they
progress together to test inhalants as a 'cofactor'. The
proposal would also give inhalants alone. Of course,
other experiments could be done in giving inhalants
first, giving virus first, or whatnot. Just because there
are several variations which could give rise to several
types of experiments is not ajustification to prevent one
among many possible experiments from being carried
out.
The last objection was the period of 6-24 months
exposures for mice. The objection states: 'Twenty-four
months is a very large part of the total life span of lab-
oratory mice. Many mice may not survive the exper-
iment'. But results would already have been obtained
for exposures of 6 months, and pushing the exposures
to 24 months would not invalidate the results for 6
months, so the logic of the objection is defective. In
addition, cancer studies on mice which routinely study
mice for periods up to 24 months are routinely funded.
Therefore recommending that the proposal not be fund-
ed partly because the period exposure for mice goes up
to 24 months is an illegitimate recommendation.
3. Journalistic treatment of the case by Science
In his letter to the National Institute on Drug Abuse,
Koshland recognized the scientific and public inter-
est of the proposed experiments. He wrote explicitly:
'I believe that this research would add much to our
understanding of AIDS, and I have told Duesberg that
I would consider such data important material for read-
ers of Science if it develops appropriately' .
As of now, the material can't develop because it
is obstructed by the National Institute on Drug Abuse
and its referees.
Not having seen any report on these matters in Sci-
ence, I contacted Science's news editor Ellis Rubin-
stein. In a letter dated 19 January, 1994, I informed
him of the above events. I thought that the difficulties
Duesberg was experiencing documented an important
case of someone wanting to do an experiment which
might raise questions about the current prevalent dog-
ma on HIV and AIDS, but not being able to get funded.
I added the comment that an appropriate news report
in Science about these events would be especially rel-
evant because Science's own editor urged the fund-
ing.
Following my letter, Science reporter Jon Cohen
contacted Duesberg on the phone, and also wrote him
on 8 February that he was interested in doing a story
about the rejected grant proposal. Jon Cohen stated:
'The main question I have is this: Are the reviewers'
criticisms unjustified? .. Any story I might do I'm sure
would hinge on that question'. In response, Duesberg
submitted the names of four toxicologists whom Cohen
might contact to get their views.
On 21 March 1994, Jon Cohen wrote back to Dues-
berg that he contacted six 'researchers' about the grant
proposal, and that three wrote back. Cohen enclosed
their signed comments. Cohen also stated that two
others told him verbally of 'problems' they had with
the proposal, and the sixth did not reply. According
to Duesberg, Cohen gave him the names of all six
(including Gallo, who was one of the two expressing
his 'problems' only verbally). Four out of the six were
retrovirologists. Duesberg commented that he would
consider' none of these retrovirologists appropriate for
reviewing a toxicology proposal such as the one he
presented. Duesberg's list of four toxicologists was
recommended to him by Harry Haverkos or by Otto
Raabe. Cohen chose only one of them. In any case, the
'researchers' consulted by Cohen effectively became
reviewers for Science.

On the basis of the reviews he got, Cohen wrote to
Duesberg that he 'did not see a story for Science about
the NIH not funding' the proposal. Cohen's letter to
Duesberg was under a SCIENCE letterhead.
The comments of the one 'researcher' who had
been recommended by Duesberg, say Reviewer RI,
were mostly favorable, although mentioning 'deficien-
cies in detail'. As mentioned previously, Reviewer RI
is a toxicologist. The overall conclusion from reviewer
Rl was as follows:
Reviewer Rl. Conclusions. I think it is impor-
tant that NE be tested for carcinogenicity in ani-
mals with and without infection with a retrovirus.
I think the investigators could perform these tests
if they did some preliminary studies and if they
first answered the criticisms in a future revised
application. Hence, I think a revision of the grant
could well be fundable. I consider that a judge-
ment of 'not recommended for further considera-
tion' is harsh and unfair, and is partly based on
wrong premises as noted above. This judgement
may indeed prevent a useful research project from
being carried out. I disagree with most of the views
of Dr. Duesberg about the causes of AIDS, but hope
that he is sufficient of an objective scientist to per-
form the tests properly (ifhe revises the application
and does some preliminary studies) and hope that
he will report the results promptly whether or not
they support his views. (He does state that he will
report the results whichever way they turn out.)
The other two 'researchers' who wrote back were
not among those suggested by Duesberg. One of them
was extremely unfavorable. I quote from what he wrote
to Jon Cohen.
Reviewer R2. I must assume that the average qual-
ity of NIMD grants is as high as those funded by
NIAID. On this assumption, if! submitted an appli-
cation of this standard to NIAID, I would not expect
it to be funded. The overall content is very meager.
Firstly, the background section is strongly biased
toward a particular hypothesis and either ignores
or minimally discusses contrary views ...
Kaposi's sarcoma is a focus of this applica-
tion. There is reasonable, but not overwhelm-
ing evidence for an infectious agent other than
HIV that causes KS. The pathogenic effects of
such a microbe may be facilitated by HIV-induced
immunosuppression, and it is possible that HIV
may also promote the development of KS direct-
ly. Oral-fecal contact has been linked with later
301
KS development, perhaps due to microbe transmis-
sion, and such sexual activities may be associated
with nitrite usage. But there is no compelling evi-
dence that KS, or AIDS, is caused by nitrite usage
per se ...
... But is this proposal going to prove that
nitrites cause AIDS or AIDS-defining illnesses
such as KS? I very much doubt it ... dosing mice
chronically with compounds does not prove that
the same conditions will be found during 'normal'
human usage. The toxicological limitations of the
experiments have been pointed out by the study
section; I am not qualified to assess the validity of
the objections, but they seem reasonable ...
In short, this proposal suffers from a poorly
justified hypothesis, a shortage of preliminary data
and a very sketchy set of experimental proposals
that would never in themselves achieve the aim of
proving nitrite usage to cause AIDS ... I am con-
vinced that the study section has reviewed the grant
application appropriately and professionally ...
Reviewer R2 also made extremely strong com-
ments against Koshland's letter supporting Duesberg's
grant application, and the propriety of such support.
Short of reproducing both letters in full, which I can-
not do for a number of reasons, I do not want to
quote from those comments because readers would not
have the full context for these comments (that is both
Koshland's letter and Reviewer R2's full comments)
to verify their legitimacy.
The third review shuffled back and forth. Excerpts
from it will give its gist.
Reviewer R3. I agree with Dr. Koshland's letter
that Duesberg should have an opportunity to exper-
imentally defend his proposal that nitrite inhalants
are important factors (or co-factors) in immuno-
suppression, K.S. andlor AIDS. I am not sure that
without some preliminary data from his lab, as well
as evidence that the collaboration set up with Otto
Raabe is workable, that the application is worthy
of funding. The Study Section Summary Statement
also correctly notes that the design of the mouse
experiments is not clear. Based on these considera-
tions, I think that Peter himself as a reviewer would
not support what might be considered as a 'fishing
expedition' .
On the other hand, some of the points in the
grant application are noteworthy of study, e.g.,
determining appropriate doses of nitrite inhalants
in mice that can be validly used to study their
302
immunotoxic potential. However, I am not a toxi-
cologist and would defer to such expertise on this
point, as well as on which nitrite derivatives are
best to utilize.
In summary, Duesberg raises a highly relevant
and important set of experiments that he and his
group have the capability to perform; however, the
lack of preliminary data and clear rationale would
generate only moderate enthusiasm for funding at
this time. On the specific issue of whether the
application should have been 'not recommended
for further consideration' (NERF), that is a judge-
ment call. I would not have gone that far based
on my limited reading of the proposal; however,
if I were present at the actual review, listening to
the primary and secondary reviewers, there might
have been enough concerns raised that I may have
supported the NERF view.
4. Some comments
I shall comment on statements by Reviewers R2 and
R3. These comments merely give a sample of my
objections to their evaluations.
(a) Reviewer R2 asserts: 'Firstly, the background sec-
tion is strongly biased toward a particular hypothe-
sis and either ignores or minimally discusses other
views'.
So what? It is not the responsibility of the propos-
al to discuss other views in a major way. The point
of the experiments is to test some aspects of the par-
ticular drug hypothesis. However, it is important that
other hypotheses were not disregarded in the proposal,
because the experiments would be conducted on con-
trol groups of mice, some of which would be infected
with Moloney leukemia virus and some of which would
not. This virus is claimed to cause mouse AIDS.
(b) Reviewer R2 asserts: 'But there is no compelling
evidence that KS, or AIDS, is caused by nitrite
usage per se' .
So what? In the statement preceding this asser-
tion, Reviewer R2 accepted that 'there is reasonable,
but not overwhelming evidence for another infectious
agent other than HIV that causes KS'. So according to
Reviewer R2 the evidence that KS is caused by HIV
is also not compelling. Is this a reason not to per-
form further experiments to test the extent to which
HIV does or does not cause KS or AIDS? The medical
establishment has tried for a decade to determine the
pathogenesis of HIV, without success. The people who
support the HIV-AIDS hypothesis have only epidemi-
ological evidence (for whatever it's worth), which is
not compelling.
There is also non compelling evidence that KS, or
AIDS, are not caused by nitrite usage per se. If there
was compelling evidence that nitrite use causes KS
or AIDS, there would be no need to do experiments
about it. 3 Conversely, preventing such experiments
from being performed prevents evidence, compelling
or otherwise, from developing one way or the other. As
a scientist, I object to the a priori obstruction placed
in the way of experiments to investigate the possibility
that nitrite usage per se may cause KS or AIDS.
(c) Reviewer R2 asks the question: 'But is this proposal
going to prove that nitrites cause AIDS or AIDS
defining illnesses such as KS?' and asserts: 'I very
much doubt it' .
Indeed, the proposal makes no claim as to what it's
going to prove. One cannot determine what a proposal
is 'going to prove' before having made the experi-
ments. The experiments themselves could have incon-
clusive results, for various reasons, thus not 'proving'
anything except that a certain set of results is inconclu-
sive. Even if all experiments eventually show a unifor-
mity that after taking poppers in sufficient quantity for
a sufficiently long period, mice develop immunodefi-
ciencies or cancer type diseases, the experiments still
would not 'prove that nitrites cause AIDS' in human
beings when taken in sufficient quantities for a suffi-
ciently long period (possibly not the same period as for
mice). Thus, speaking for myself, I don't 'very much
doubt' that the experiments 'will prove that nitrites
cause AIDS or AIDS related diseases'. I know they
will 'prove' no such thing, defectively formulated in
such absolute generality by Reviewer R2.
However, the experiments might suggest others;
they might be preliminaries for further experiments,
on other animals, varying circumstances or whatever.
That's what experiments are for, to test various ranges
of validity of various hypotheses. If the experiments
systematically show the above uniformity, they might
also open some people's minds to consider more seri-
ously the possibility (not certainty) that nitrites may
cause AIDS related diseases in human beings. Con-
3 The need for such experiments was explicitly recognized in
NIDA's 'Summary Statement', which I have already quoted to the
effect that 'the major strength of this proposal is that it addresses
the important public health problems of whether nitrite abuse acts as
a cofactor in AIDS pathogenesis and if nitrites can cause Kaposi's
sarcoma in the absence of retrovirus infection'.

versely, if they turn out inconclusive or show an oppo-
site uniformity, they might have the opposite effect.
The effect of the experiments will depend on how they
turn out, it will be different on different people, and it
cannot be predicted in advance, partly because it will
depend on many factors in many ways.
If a reviewer's doubts that Duesberg' s proposal will
prove that nitrites cause KS or AIDS were taken as a
reason not to fund the proposal, and as a reason not to
report the matter in Science, then I object and I ask the
scientific community to evaluate the legitimacy of non-
funding and non-reporting based on such a reason.
I add one comment about the third review, concern-
ing the nature of scientific research.
Reviewer R3 writes: 'Based on these considera-
tions, I think that Peter himself as a reviewer would
not support what might be considered as a 'fishing
expedition' '.
I have several objections to this sentence. First, I
find it illegitimate to presume what 'Peter' would do,
especially since Duesberg made the proposal for the
experiments in the first place.
More fundamentally, I object to such a put-down
of 'fishing expeditions' in the scientific context, with
the innuendo contained in the term 'fishing expedi-
tions', which has been used commonly in other con-
texts. A 'fishing expedition' in the scientific context
is quite different from a political context when some
parts of a political establishment go on a 'fishing expe-
dition' against people with a different political opinion.
I think 'fishing expeditions' against the great mysteries
of nature are the essence of original scientific research.
I agree with Koshland that the material of Duesberg's
experiments would be of great interest for readers of
Science if, as Koshland writes, 'this material devel-
ops appropriately'; and I think the material would be
of great interest to other scientists and to the public
as well. Having the material in Science (if it develops
appropriately) would be just a start. But we can't know
how the material will develop if the development is
obstructed a priori by funding agencies.
5. A NIDA meeting on nitrite inhalants
On 23-24 May 1994, the National Institute for Drug
Abuse (NIDA) sponsored a meeting to discuss 'the role
of nitrite inhalants in AIDS, particularly in its most vis-
ible expression, Kaposi's sarcoma'. This meeting was
reported in the article 'NIH reconsiders nitrites' link
303
to AIDS' (Biotechnology, 12 August 1994, p. 762).
I have given an account of this article elsewhere at
greater length (,HIV and AIDS: Questions of Scien-
tific and Journalistic Responsibility', Yale Scientific,
November 1994), but it is relevant to report here an
about-face by Gallo. The Biotechnology article stat-
ed:
'Finally, Robert Gallo of the National Institutes of
Health (NIH, Bethesda, MD) surprised some atten-
dees and panelists by arguing that HIV is not the
primary cause ofKS [Kaposi's Sarcoma], although
it may aggravate the condition once KS is caused
by 'something else'. As to what that something
else might be, Gallo favored a microbe that has yet
to be discovered, though he allowed that carcino-
genic nitrites could well be a primary cause. In the
true spirit of scientific inquiry, quite different from
the rancor of prior discussions of alternative caus-
es of AIDS, Gallo called for funding of Duesberg's
nitrite experiments'.
Question: Did Gallo inform Science and Jon Cohen of
his changed position about the funding of Duesberg's
nitrite experiments? Do the editors of Science and its
reporters read Biotechnology? I sent them a copy of the
above article when it appeared. 4 In addition, Koshland
wrote another letter on 24 August 1994, iterating his
support of funding for Duesberg's experiments.
6. Developments in fall 1994
The first version of the present article was sent to edi-
tors of Science in spring 1994, among many others on
the 'cc list'. In September 1994, I had a major mailing
containing an updated version, together with my article
on 'HIV and AIDS .. .'. Both were then accepted for
publication by the Yale Scientific, with the 'HIV and
4 Actually, this statement of Gallo was subsequently nullified. In
an interview with The Scientist (14 November 1994), answering a
question whether the Biotechnologyarticle was 'accurately reporting
his views', Gallo said: 'They were. But listen carefully. The proposal
that Duesberg made in front of me at a Kaposi's sarcoma [KS]
meeting that was organized by the popper people I thought was a
reasonable idea. But that doesn't mean that I saw the thing written
up and that it was written up properly'. The Scientist interview
with Gallo on 14 November was published along with an article
on an AIDS conference celebrating Gallo's lab. The article was
entitled: 'Gallo's Meeting: A Scientific Folk Festival'. These two
items (article and interview) exist as part of the record. I found
both exceedingly tendentious, and suppressive of much information
which would give a quite different aspect to the questions covered
by these two pieces, but here is not the place to document the
tendentious and defective journalism of The Scientist.
304
AIDS .. .' article to appear in November, while the
'funding' article would appear in the next issue, Jan-
uary 1995. Science editors and reporters again were on
the mailing list for my September mailing to about 100
people. With these mailings I was attempting to fill the
information vacuum which resulted from Jon Cohen
informing Duesberg under a 'SCIENCE' letterhead
that he did 'not see a story for Science about NIH not
funding' Duesberg's proposal. I was also attempting to
put pressure on Science to report various events.
In October 1994, Jon Cohen asked Duesberg for an
interview to be used in an article for Science. Duesberg
accepted, provided Cohen's questions were put first
in writing. Duesberg would then also answer in writ-
ing, and Duesberg accepted having a verbal exchange
afterwards. All of these took place. Cohen submit-
ted a first batch of questions 10 single-space pages
long, which Duesberg answered point by point in 11
single-space pages. Cohen submitted a second batch
of questions again 10 single-space pages long, which
Duesberg answered in 7 single-space pages. The sub-
sequent verbal exchange was several hours long.
Duesberg had some objections to the way Cohen's
questions were put together, since they all assumed
implicitly that HIV is the cause of AIDS. The ques-
tions prejudiced the issue toward the HIV causality. To
a large extent, Cohen was asking Duesberg to comment
on some scientific articles purporting to show or to sup-
port the causal relation of HIV and AIDS. The ques-
tions were detailed and specialized. Duesberg found
that most of the points raised by Cohen were in effect
already answered in two papers of his (' AIDS acquired
by drug consumption and other noncontagious risk fac-
tors' , Pharmacology & Therapeutics 55: 201-277; and
'Human immunodeficiency virus and acquired immun-
odeficiency syndrome: Correlation but not causation',
Proc. Natl. Acad. Sci. USA 86: 755-764). In these
papers, among other things, Duesberg cited much sci-
entific literature, but he did not and could not cite the
entire literature. However, Duesberg claimed that the
articles he cited were typical, and he analyzed many
common defects in the current literature about HIV
and AIDS. Cf. Appendix 1 below, which reproduces a
list of the specific objections to certain scientific arti-
cles noted by Duesberg in a letter to Cohen dated 20
October 1994.
Cohen also asked why Duesberg had not cited other
articles which Cohen submitted for his consideration.
In fact, some of the articles brought up by Cohen had
not appeared at the time of publication of the Phar-
mac. Ther. and PNAS papers cited above. The defects
analyzed by Duesberg in these papers were similar to
defects which he found in the articles brought up by
Cohen.
My article in the Yale Scientific appeared in the
middle of November, and I distributed several hun-
dred copies, including half a dozen copies to various
people at Science. After internal consultations and revi-
sions, a final version of Cohen's article appeared in Sci-
ence, 9 December 1994, under the title 'The Duesberg
Phenomenon'. In this article, Jon Cohen stated: 'But
because the Duesberg phenomenon has not gone away
and may be growing, Science decided this was a good
time to examine Duesberg's main claims'. Thus Sci-
ence and Jon Cohen changed their mind between spring
1994 and fall 1994. In this published version, Cohen
finally reported Koshland's support as follows: 'Also
unpersuaded of Duesberg's ideas - but persuaded he
shouldn't be shut out of scientific resources - is Daniel
Koshland Jr., editor-in-chief of Science, who has writ-
ten letters to the National Institute on Drug Abuse sup-
porting Duesberg's recent grant proposals'.
Nevertheless, as of December 1994, all recent
applications by Duesberg for funding of his lab were
rejected. This was correctly reported by Cohen, who
wrote: 'In addition, Duesberg has been turned down
by funding agencies on several new proposals to study
both AIDS and cancer' . Cf. Appendix 2 for a summary
of these proposals.
A subsequent article by Jon Cohen in Science on 16
December, 1994 reported on the possibility of a new
virus causing Kaposi's sarcoma (cf. my article 'HIV
and AIDS .. .', §6). In a letter to the editors sent 4
January 1995, Duesberg stated:
Science wonders (16 Dec., p. 1803) about the 'mys-
tery' that 'KS is almost exclusively confined to
male homosexuals' ....
1) Since nitrites are some of the best known
mutagens and carcinogens (3), I propose the fol-
lowing experiment to solve the 'mystery': Expose
100 mice, or cats, or monkeys to nitrite inhalants
at doses comparable with human recreational use
and for time periods approximating the so-called
lO-year latent period between infection by HIV to
the onset of AIDS - possibly a euphemism for the
time of drug use necessary for AIDS to develop. (It
takes 10 to 20 years of smoking for emphysema or
lung cancer to develop.) I would predict this result:
Immunodeficiency, pneumonia, and pulmonary KS
in animals.

2) I also propose to 'mainstream AIDS
researchers' an easy epidemiological experiment
to test my hypothesis that HIV is not the cause
of AIDS. According to Science, these researchers
argue that it is 'impossible' to eliminate confound-
ing factors from HIV in typical AIDS risk groups,
as for example in hemophiliacs 'because [they]
do not keep track of each factor VIII treatment'
(9 Dec., p. 1645). Therefore I propose to com-
pare the incidence of AIDS-defining diseases in
3650 homo- or heterosexual American men, who
are not on transfusions and recreational drugs or
AZT, but are HIV-positive, to the incidence in 3650
HIV-negative counterparts. These healthy subjects
could be found by the U.S. Army, which tests over
2.5 million per year, or among those contributing to
the blood banks, which test over 12 million a year.
If the 3650-day latent period is correct, every 2
days one of the people that are HIV positive would
develop AIDS. I would predict this result: The per-
centage incidence in the HIV-positive group will
be the same as in the HIV-negative group.
If the mainstream AIDS researchers are not
already doing these experiments, I would be
delighted to do them provided I could get fund-
ed.
At the time this article goes in production, Duesberg
was not funded.
The scientific community is entitled to know ofthe
events I have reported above, both concerning the non-
funding by NIH and the circumstances under which
Science reports or does not report events.
References
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CDC, 1985. Revision of the case definition of acquired immunodefi-
ciency syndrome for national reporting - United States, Morbid.
Mortal. Week. Rep. 34, pp. 373-375.
Fee, E. & D. Fox, 1990. AIDS - The Making of a Chronic Disease.
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Haverkos, H., 1988. Kaposi's Sarcoma and Nitrite inhalants. Psy-
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AIDS. Edited by T. Peter Bridge et al., Raven Press, New York,
pp.165-172.
Haverkos, H. & 1. Dougherty, 1988 (eds.) Health Hazards of Nitrite
Inhalants. HHS Public Health Services, NIDA, 5600 Fishers
Lane, Rockville MD 20857.
305
Appendix 1. Excerpt from a letter from Peter
Duesberg to Science reporter John Cohen October
20,1994
The results in the HIV-AIDS papers, on which you ask
me to comment and which form the basis of your ques-
tions, are entirely similar to the results in papers I cited
in my articles, and they suffer from similar defects.
The defects of these HIV-AIDS papers include:
(1) discarding a priori other possible causes of
AIDS (whatever it is) besides HIV;
(2) not measuring lifetime use of foreign proteins
transfused or of drugs consumed in AIDS risk groups
and patients;
(3) not comparing morbidity and mortality of HIV-
positive drug users, transfusion recipients and other
risk groups to matched HIV-negatives;
(4) obscuring the role of certain factors, notably
drugs and foreign proteins, by averaging certain results
for people who may have used drugs only a short
time, with those who have used drugs for a decade
or more;
(5) failure to determine annual AIDS risks of HIV-
positive persons of different risk groups and countries.
Instead cumulative AIDS statistics are reported, and
these always go up;
(6) failure to determine whether outside the known
AIDS risk groups, AIDS has increased mortality and
morbidity of the general population in any country, or
whether it is a new name for the normal background of
these diseases. This is a consequence of not comparing
the morbidity and mortality of HIV-positives to HIV-
negatives in the general population. For example, the
rare coincidence of HIV and pneumonia in persons
of the general populations must be shown to exceed
the normal background of AIDS-defining diseases in a
given risk group before it can be considered evidence
for HIV causing AIDS;
(7) failure to consider that all AIDS-defining dis-
eases are previously known diseases that occur at a
low rate in all people and at a higher rate in AIDS risk
groups;
(8) using the circular AIDS definition. That is
to report AIDS-defining diseases in HIV-positives as
AIDS, and either not to report clinically diagnosed
AIDS diseases in HIV-negatives or not to report 90n-
troIs at all;
(9) failure to recognize that 'AIDS tests' detect
antiviral immunity which is a prognosis against rather
than for an HIV-disease, if such a disease exists;
306
(10) failure to distinguish between infectious and
thus potentially pathogenic HN, and DNA or RNA of
latent HIV, or even antiviral antibodies which have no
known pathogenic potential;
(11) failure to account for the unpredictable latent
periods from HN infection to AIDS, that are claimed
to range from 10 months to over 10 years. These long
latent periods are totally incompatible with the short
generation time of HIV, which is only 24 to 48 h.
(12) complete refusal to consider the simplest and
most plausible HIV hypothesis - namely that HN is a
harmless passenger virus. The criteria of a passenger
virus: (i) the time of infection is irrelevant to the onset
of disease; (ii) the passenger virus can be either active
or passive during the course of the disease; (iii) the
passenger virus can be completely absent during the
disease. HN meets all criteria of a passenger in AIDS
perfectly;
(13) failure to report the toxicity and lifetime
dosage of anti viral drugs like AZT, and failure to report
AZT compensating, lifesaving treatments like transfu-
sions.
Appendix 2. List of rejected grant applications by
Duesberg
[1 reproduce below excerpts from a letter dated 6
December, 1994, which Duesberg wrote to me. 1
had no further time to look into the references and
letters he gave me accompanying his summary, the
way 1 looked previously into the reports from the
reviewers for Jon Cohen. S.L.]
Cancer grants
(1) In 1990, the competing renewal of my Outstand-
ing Investigator Grant (OIG), 'Retroviral onc genes
and cellular proto-onc genes' was turned down. This
type of grant h"d been awarded in 1985 to only about
a dozen outstanding scientists for a 7 year term. My
grant resulted in 86 publications, including research
papers, theoretical papers, reviews and reports during
its term period.
The pink sheet of the mail ballot review of this
renewal application said in Oct. 1990: ' ... his produc-
tivity has been a bit lower and his science, although
still solid, is not as sharp and imaginative as before',
' ... much of the investigator's time and effort during
the past period has been occupied by theoretical issues
pertinent to his research and other interests'. (copy
enclosed)
This decision was appealed on two grounds: 1)
Three of the reviewers listed on the pink sheet as hav-
ing participated in the review never reviewed the appli-
cation .... 2) At least two reviewers had personal and
commercial conflicts of interest. . . . After a lengthy
correspondence with the NIH and the administration of
UC Berkeley, UCB signed a rare appeal to the NIH in
March 1992 to re-review my application. This appeal
was granted in the spring of 1993 (see letter by Dr.
Blair from the NIH).
(2) In May 1993 my appeal of the orG review was
turned down by the Experimental Virology Study Sec-
tion of the NIH with a nonfundable priority: 'Appli-
cant whose productivity has recently diminished both
in quantity and most disturbingly in qUality ... a vast
amount of highly relevant work from other laborato-
ries is neither acknowledged nor incorporated into the
proposal' (pink sheet enclosed).
(3) In May 1993 an application to the Tobbaco-
Related Disease Research Program (TRDR) of the
University of California, entitled 'The role of chromo-
some abnormalities in cancer' was accepted but with
the priority score of only 8% (letter enclosed).
(4) In May 1994 a revised application to the same
TRDRP again entitled 'The role of chromosome abnor-
malities in cancer' was rejected with the non fundable
priority 'Not recommended for further consideration'
(letter enclosed).
(5) In July 1994, a revised application entitled
'The role of chromosome abnormalities in cancer'
was ranked in the bottom 10% by the American Can-
cer Society and was not approved for funding (letter
enclosed).
(6) In December 1992 a postdoctoral grant applica-
tion was submitted to the Cancer Research Coordinat-
ing Committee of the University of California entitled
'The role of chromosome abnormalities in cancer' . The
application was not funded according to a letter from
May 1993 (enclosed).
(7) In December 1993, a postdoctoral grant applica-
tion was submitted to the Cancer Research Coordinat-
ing Committee of the University of California entitled
'Cancer caused by chromosome abnormalities?' The
application was not funded according to a letter from
May 1994 (enclosed).
(8) In December 1994 a new postdoctoral grant
application was submitted to the Cancer Research
Coordinating Committee of the University of Califor-

nia entitled 'The role of chromosome imbalance in
cancer' .
AIDS grants
(9) In February 1993 a grant application was made
to the Universitywide Aids Research Program of the
University of California entitled 'Animal test of the
hypothesis that amyl nitrites cause AIDS'. The appli-
cation was ranked 'within the fourth quartile'. With
regard to its approval a split vote with five for and four
against was reported (see enclosed letter).
(10) In August 1993 an application was made to
the National Institute of Drug Abuse (NIDA) entitled
307
'Animal tests of the AIDS risks of nitrite inhalants'.
The application was accompanied by an endorsement
from Dan Koshland, editor of Science. The application
was 'not recommended for further consideration' in a
letter from the NIDA of January 1994 (enclosed).
(11) In August 1994 a revised application was
made to the National Institute of Drug Abuse enti-
tled again 'Animal tests of the AIDS risks of nitrite
inhalants'. The application was accompanied by an
endorsement from Dan Koshland, editor of Science.
Today I received a letter dated November 30, 1994,
that the initial review group has recommended again
'NO FURTHER CONSIDERATION BE GIVEN TO
THIS APPLICATION' (enclosed).
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 309-313, 1996.
© 1996 Kluwer Academic Publishers.
mv Symposium at AAAS Conference
John Lauritsen
26 St. Mark's Place, New York, NY 10003, USA
The HIV-AIDS hypothesis was debated on 21 June
1994, at a day-long symposium in San Francisco, spon-
sored by the Pacific Division of the American Associ-
ati9n for the Advancement of Science (AAAS).
The symposium, 'The Role of HIV in AIDS: Why
There is Still a Controversy' , was organized by Charles
Geshekter, Professor of History at California State
University, Chico. Dissatisfied with previous AIDS
sessions - 'consensual gabfests' in which only one
point of view was presented - he began in 1993 to put
together an interdisciplinary panel of scientists crit-
ical of AIDS orthodoxy. The Executive Committee
of the Pacific Division AAAS approved the sympo-
sium, including the list of speakers, at its January 1994
meeting, and the final program was reviewed by the
Executive Director of the Division in early April.
Then, in mid-May, an intense flak campaign erupt-
ed. Two AIDS researchers, Warren Winkelstein and
William Ascher at Berkeley, put pressure on the AAAS
to cancel the program. The San Francisco Chronicle
ran an article by Science Editor David Perlman with the
headline: 'AIDS REBELS TRY TO STEAL SHOW:
But Scientists Stymie Plan By Mavericks Who Deny
HIV Link'. A similar article appeared in the popular
British science magazine Nature.
Control over the symposium was taken away from
Geshekter, without his consent or knowledge, by other
AAAS officials. Seven pro-HIV speakers were added
to the program, along with two 90-minute panels com-
posed entirely of defenders of AIDS-orthodoxy.
Fortunately, on the day of the symposium Geshek-
ter regained control, and the final panel included all of
the speakers.
Phillip Johnson
The first speaker was Berkeley Law Professor Phillip
Johnson, on 'The role of HIV in AIDS: Why there
is still a controversy'. According to Johnson, AIDS
researchers themselves now admit they are at an
309
impasse. They cannot explain how HIV could be
responsible for the mass destruction of T4 cells, when
it infects only a minuscule number of them. Official
explanations of how HIV might cause illness have
become ever more complicated and fanciful.
Johnson criticized the question 'What causes
AIDS?' as being overly general, and bearing with it
the unwarranted assumption that all AIDS diseases, in
all countries and all risk groups, are one and the same
thing. Instead he proposed focussing on more specif-
ic questions, for example: '(1) What is the cause of
Kaposi's sarcoma? and (2) What is really known about
the role of HIV in causing disease in Africa?'
Johnson's salient points on KS were: 1) KS occurs
not infrequently in gay men who are negative on the
HIV-antibody test, and 2) Robert Gallo and other AIDS
researchers now concede that HIV is not the cause of
KS. He posed the question:
If KS is not caused by HIV, and if many other
AIDS-defining conditions occur both in the pres-
ence of mv and in its absence, should we not
reconsider the definition of the syndrome, and
hence the role ofHIV in AIDS?
With regard to AIDS in Africa, Johnson described
the lack of testing in making AIDS diagnoses, the
extreme unreliability of the tests even when they are
used, the shoddy epidemiological studies conducted
there.
He concluded:
For essentially political reasons, HIV science has
been ruled by unexamined assumptions. It is time
at long last to have the scientific debate that wasn't
allowed to occur ten years ago. Let the politics be
put aside, and let the science begin.
Harvey Bialy
Harvey Bialy, a molecular biologist and Research Edi-
tor of BioTechnology, spoke on 'HIV-AIDS: A hundred
thousand papers and no proof'. He began by artic-
310
ulating and then demolishing a 1984 version of the
HIV-AIDS hypothesis: 'HIV, a new, mutant retrovirus,
causes AIDS by killing CD4+ lymphocytes'.
Ordinary retroviruses are not pathogenic; however,
there is no evidence that HIV is mutant. Bialy showed
a genetic map of HIV, and said: 'For all intents and
purposes this could be the map of 50 other retrovirus-
es'.
Does HIV kill CD4 cells? 'It certainly doesn't kill
the T cell lines that are used to produce kilograms of
the virus for the AIDS industries' .
Since the 1984 version is clearly untenable, Bialy
reformulated (with irony) the HlV-AIDS hypothesis:
'HIV, an established, conventional retrovirus, causes
AIDS by killing CD4+ lymphocytes by mechanisms
previously and presently unknown to virology'. Even
so, the hypothesis is unable to explain the long and
unpredictable incubation period between infection and
disease, the biochemical quiescence of the virus, and
its inability to cause any disease whatever in chim-
panzees (who are nevertheless fully susceptible to HIV
infection).
Celia Farber
Celia Farber, whose AIDS column in SPIN has run for
over six years, spoke on 'AIDS as a mirage of modern
media: How the media reconstruct reality in the Infor-
mation Age'. She discussed 'totalitarian AIDS sci-
ence' , a 'self-righteous campaign to stamp out debate',
maintaining that people had become 'hypnotized by the
extremely powerful, red ribbon-wearing Zeitgeist' , by
'self- appointed 'AIDS professionals' .
Charles Thomas
Charles Thomas, head of the Helicon Foundation,
spoke on 'The marketing of AIDS and other apoca-
lyptic visions'. His premise was that AIDS needs to be
understood in the context of 'scary science' - the off-
spring of mass psychology and the funding demands
of specialized government bureaucracies. Among cur-
rent Scientific Scares he cited nuclear power plants,
pesticides, pollution, global warming, ozone holes,
asteroids, acid rain and AIDS.
Though one or more of these might have some basis
in reality, they have certain common features. They
are mysterious, they place everyone at risk, and they
require highly specialized experts, powerful bureau-
cracies, and a national response with an abundant flow
of tax dollars. All can be understood as requirements
for getting funding.
Maintaining that Scientific Scares are only partly,
and dubiously, scientific, Thomas suggested an ele-
gantly simple solution for the AIDS problem: cut off
the funding:
These Scientific Scares are what might be named
'political diseases' and they are not susceptible to
scientific refutation. However, they can be cured by
cutting off their supply of money. Consider the fol-
lowing 'thought experiment': Imagine the present
$6 billion that goes annually to AIDS research edu-
cation, treatment, etc. being reduced sharply to
ZERO. There would be howls, of course, but AIDS
would disappear in two weeks. In its place would
be the component diseases that were swept under
the common rug and given the name AIDS. These
separate diseases would be treated as such, and the
(former) AIDS patients and the rest of America
would be much better off.
Peter Duesberg
Peter Duesberg, Professor of Molecular Biology at
Berkeley, spoke on 'The drug-AIDS hypothesis' . After
discussing the formation of belief systems, he posed a
series of rhetorical questions. Would we have accept-
ed the HlV-AIDS hypothesis ten years ago if we had
known then:
- that AIDS would not explode into the general,
sexually active population?
- that prostitutes would not get AIDS from their
clients, or vice versa? Or health care workers from
their patients, or vice versa?
- that not even one Kaposi's sarcoma has been
transmitted through a blood transfusion?
- that HlV replicates within 24 hours, very much
like all other viruses, but allegedly causes a disease
only ten years later?
Duesberg laid open the most fundamental premise
of the AIDS construct, that all of the 29 (at last count)
AIDS-indicator diseases are caused by a condition of
'immune deficiency' caused by HIV infection. In fact,
only about 61 % of all U.S. and European AIDS cases
have anything to do with immune deficiency.
As an alternative to the HIV-AIDS hypothe-
sis, Duesberg presented his own DRUGS-AIDS
HYPOTHESIS, which states:
'AIDS in the U.S. and Europe is caused by the long-
term consumption of recreational drugs and AZT' .
The remaining AIDS - hemophiliacs, transfusion
recipients, and other cases from non- risk groups

- reflect the normal incidence of these diseases,
simply under a new name.
Jerold Lowenstein
Jerold Lowenstein, of the University of California
Medical Center in San Francisco, was the first of the
speakers added to the symposium to achieve 'balance' .
He spoke on 'The medical and scientific evidence for
HIV being the cause of AIDS'.
He did not, in fact, present a reasoned argument,
backed by evidence, that HIV was the cause of AIDS,
nor did he acknowledge the points made by the previ-
ous speakers. He stated:
At the present time it appears that all AIDS patients
throughout the world are infected with HIV, and
nearly all HIV-positive individuals will eventually
get AIDS - although there does seem to be a small
subset who escape that fate.
This statement is completely untrue. Even Gallo
and Montagnier now admit that most HIV-antibody-
positive individuals will not get sick.
Lowenstein talked about 'several different pat-
terns of AIDS throughout the world' - totally ignor-
ing the arguments previously made by Phillip John-
son, Harvey Bialy, and Peter Duesberg, that Euro-
pean/American AIDS and African AIDS are clearly
two different epidemics, with different epidemiolo-
gies, diseases and causes.
And he talked about SIV (Simian Immunodeficien-
cy Virus), which causes illness in monkeys in captiv-
ity. He did not, however, talk about HIV in monkeys,
which would have been relevant but damaging to his
case.
Lowenstein's conclusion consisted of unfounded
assertions:
'In conclusion: the reason why I and 99% of my
colleagues are convinced that HIV is the cause of
AIDS is that all AIDS patients are infected with
HIV, virtually all HIV-positive individuals will get
AIDS ... and finally, health care workers with no
other risk factors get AIDS from accidental needle-
sticks - there are several dozen such cases'.
Discussion
In the discussion period, Lowenstein was reprimanded
by other panelists and by members of the audience for
having insinuated that AIDS critics were believers in
'conspiracy theories'. Time and again he was asked to
provide references for assertions he had made, and he
was either unwilling or unable to do so.
311
Molecular biologist Harry Rubin pointed out that
Lowenstein's slides failed to distinguish between the
spread of HIV and the spread of AIDS. Taking issue
with Lowenstein's claim that 99% of his colleagues
were convinced of the HIV-AIDS etiology, Rubin said
that his own colleagues were 'pretty confused and
uncertain' . Rubin stated that the rapid rise in heterosex-
ual AIDS cases, claimed by Lowenstein, was merely
'due to re-defining AIDS in order to maintain the pub-
lic scare that Dr. Thomas was talking about, that AIDS
is a threat to the heterosexual community' . Lowenstein
did not respond to these points.
Nor, in response to a question from Duesberg, could
Lowenstein provide a reference for his claim that acci-
dental needle-sticks had resulted in AIDS. Nor, faced
with questions from Bialy, could Lowenstein explain
why he had showed a slide with no basis in experimen-
tal reality - nor could he provide support for his claim
that HIV replicates in and destroys T-cells.
The morning panel
The morning panel did not include critics of the HIV-
AIDS hypothesis. First was Jan Kuby, an immunol-
ogist at San Francisco State University. She talked
about autoimmunity, T-cell activation, antigens, apop-
tosis, SCID mice, cytokines, Alzheimers, etc. She
informed the audience, '98% of the T-cells are in lym-
phoid tissues, but most data is [sic] based on blood',
and asserted:
The virus is infecting cells in the lymph nodes
- massive amounts of virus are being produced
there . . . even before we can see anything going
on in the blood at all.
The above statement is simply not true. The lymph
nodes do collect viruses and viral debris - just as the
lint filterin a clothes dryer collects lint- but if 'massive
amounts of virus' were being produced anywhere in the
body, there would also be massive amounts of virus in
the blood.
Next came Michael Ascher, of the California State
Department ofHea1th Services, co-author, with Warren
Winkel stein, of an article 'Does drug use cause AIDS?'
(Nature, 11 March 1993). He ridiculed the nitrites-
KS connection. He contended that saying AZT causes
AIDS diseases is like saying insulin causes diabetes,
apparently unaware of Duesberg's extensive analysis
of AZT's toxicities.
Next came Robert Schmidt, a physician, who pre-
sented a multifactorial approach to diseases of the
312
elderly. It was a thoughtful and interesting talk, but
irrelevant to the central topic.
Peter Plumley
The first afternoon speaker, Peter Plumley, spoke on
'An actuarial analysis of the AIDS epidemic in the
United States' . His central thesis was that official AIDS
statistics, and pronouncements of the Public Health
Service, have greatly distorted and exaggerated the
epidemic, resulting in unrealistic perceptions of the
relative risk of various sexual acts. The excessive fear
of AIDS has adversely affected the lives of many peo-
ple.
KaryMullis
Kary Mullis, the 1993 Nobel Laureate in Chemistry,
addressed the enigma: Why is there no monograph
which marshals all of the arguments in favor of the
HIV-AIDS hypothesis?
Mullis asked dozens of AIDS researchers to sup-
ply him with a reference for the assertion that HIV is
the probable cause of AIDS. Some of them became
angry, and others said he didn't need a reference,
because 'everyone knows that'. Some suggested a
totally inadequate CDC report. Finally, Luc Montag-
nier came to San Diego, and Mullis thought, 'this guy
will know'.
After the meeting I asked him, and he first men-
tioned the CDC report, and I said I had already
looked at it, that it wasn't what I was looking
for - that I wanted a scientific paper that would
support the notion that HIV is the probable cause
of AIDS, not the consensus of a bunch of people
who'd already begun looking at it. He said, 'Well,
why don't you quote the SIV work'? And I said
to myself, 'Oh my god! There really isn't such
a paper, there can't be, or he wouldn't have to
refer ... to a virus that might kill a monkey ... to
illustrate the probability that HIV is the cause of
AIDS!
Harry Rubin
Harry Rubin, Professor of Molecular Biology at Berke-
ley, spoke on 'The rush to simplification of com-
plex problems in biomedical science: Cancer and
AIDS'.
Rubin described his pioneering work forty years
ago on the Rous sarcoma virus: 'The first virus identi-
fied and characterized as a retrovirus - the one that, at
least until AIDS, was the one most studied and worked
on'. As viruses of this kind had been associated since
1910 with several types of leukemia in chickens, they
were given the name Avian Leukosis Virus.
However, Rubin subsequently found that these
leukemias could and would occur in the absence of
the retroviruses. Further, among the chickens that were
infected, whose every cell was infected and constant-
ly producing virus, only 15% developed the leukosis.
'In spite of these findings, these viruses are still called
Leukemia or Leukosis viruses, as they have been for
85 years'.
Rubin then discussed cancer, concluding: 'Cancer
can only be understood at the level of the complex
dynamics of cellular interaction with the aging pro-
cess and other such considerations as diet, smoking,
lifesty Ie, etc.' .
The same basic process is at work in AIDS. 'Ifthere
ever was a case of multifactorial disease occurrence,
in my estimation, AIDS is the case' .
Bryan Ellison
Bryan Ellison is a graduate student in molecular and
cell biology in Berkeley. His talk, 'Drug use does cause
AIDS: A reappraisal of the San Francisco Men's Health
Study' , was a severe critique of the article by Michael
Ascher, Warren Winkelstein, et at.
The Ascher report claimed that AIDS and T-cell
depletion occurred only in the men who were HIV-
antibody- positive, and that drug use had no effect on
either T-cell depletion over time or the development of
AIDS.
Ellison and his colleagues obtained the raw data,
and found that Ascher et al., had seriously misreported
the data:
By ignoring huge gaps and striking selection biases
in the database, Ascher et al., reached the unsup-
portable conclusions that HIV-positive and HIV-
negative men used similar amounts of drugs and
that levels of drug use were not related to the risk
of developing AIDS. In contrast, we found that
HIV- positive men used significantly more heavy
drugs that did HIV- negatives, and that drug use
was more highly correlated with AIDS-related dis-
eases than was HIV
Ellison characterized the misreporting of data by
Ascher and Winkelstein a 'serious breach of scientific
ethics' , and called upon them to retract the paper.

Charles Geshekter
Charles Geshekter, spoke on 'rethinking the AIDS epi-
demic in Africa'. Official statistics, he maintained,
have been umeliable to the point of absurdity. Africa
is supposed to be saturated with HIV, its population
ravaged by the AIDS epidemic. And yet, since 1981
- thirteen years - there have been only 151,000 con-
firmed AIDS cases in all of Africa.
Most AIDS cases are diagnosed on clinical symp-
toms alone. The HIV antibody tests, ELISA and West-
ern Blot, are almost useless, as they cross-react with
antibodies to many diseases that are endemic to Africa.
Furthermore, the symptoms attributed to 'AIDS' are
indistinguishable from those that have plagued Africa
since the beginning of the 20th century. Geshekter
debunked the media myth that the African AIDS catas-
trophe can only be averted through the intervention of
Western science. Particularly dangerous is the pressure
to use AZT on HIV-positive Africans.
Warren Winkelstein
Warren Winkel stein, Professor of Public Health at
Berkeley, spoke on 'Inferences from epidemiological
data'. His brief talk mostly presented points from the
report he had co-authored with Michael Ascher. He
showed a slide in which none of the HIV-negative men
developed AIDS, whereas those who were either HIV-
positive upon entry into the study, or became so later,
did.
Winkelstein addressed Bryan Ellison's accusation
that at least 45 HIV- negative men had developed
313
AIDS-diseases. This was ridiculous, said Winkelstein,
because if these 45 men had really had AIDS, then
36 of them ought to have died, according to the latest
AIDS projections. However only [only!] 7 ofthem had
died.
Winkelstein's logic is faulty. No matter how sick
the 45 HIV- negative men were, they could not official-
ly have been diagnosed as having 'AIDS'. Therefore,
they would not have received a prognosis of death, and
they would not have been prescribed AZT! One could
use Winkelstein' s data to argue that an AIDS diagnosis
is deadlier than AIDS itself.
The Final Panel
For the final panel, all of the speakers came on stage.
None of the pro-HIV speakers even attempted to
rebut the dozens of arguments that had been advanced
against the HIV-AIDS hypothesis.
On the whole the event was a triumph for the side
questioning the AIDS orthodoxies. The AIDS-skeptics
achieved a critical mass, and spoke with confidence and
authority. Those who attempted to defend the official
dogmas were confused and defensive; they failed to
rebut or even acknowledge the points made by the
skeptics; in short, they put on a very poor show. It is
clear that the official AIDS experts cannot compete in
a free and open debate.
The principle of 'balance' should be applied to all
future AIDS programs. Never again should only the
HIV-AIDS point-of-view be represented.
P.H. Duesberg (ed.). AIDS: Virus- or Drug Induced? 315-323,1996.
© 1996 Kluwer Academic Publishers.
AIDS and poppers
Tom Bethell *
Once a week, Dr. Harry Haverkos puts on the white
unifonn of the Public Health Service, and goes to work
at the National Institute on Drug Abuse in Rockville,
Maryland. It is one of over 40 divisions comprising
the National Institutes of Health. Dr. Haverkos, 43,
is the director of the Office of AIDS at NIDA, and
although he is a cautious man, not given to dramatic
statements, he is persistent, and for over ten years he
has been pursuing a line of inquiry about AIDS that
has received remarkably little attention considering its
potential importance.
Since 1983, when he was working at the Centers for
Disease Control in Atlanta (CDC), and began analyz-
ing the early data on AIDS, he has been intrigued by the
possible role of a widely abused drug called poppers.
A nitrite-based inhalant, it just may be a missing key to
the endless medical puzzle called AIDS. In particular,
Haverkos believes that the drug may be the myste-
rious cause of Kaposi's sarcoma (KS), the rare fonn
of cancer that, at the outset of the epidemic, almost
defined AIDS. 'It's clear thatHIV alone can't explain
Kaposi's,' he said. 'There has to be something else'
(Haverkos, 1994).
Haverkos's career with the Public Health Service
was launched just as AIDS was discovered. A Notre
Dame graduate, he attended the Medical College of
Ohio in Toledo, and did his intern residency at Akron
City Hospital. Then, in July, 1981, he joined the CDC
in Atlanta. Something new and strange was happen-
ing in the homosexual communities on both the East
and West Coasts. Young homosexuals, apparently in
good health, were coming down with previously rare
diseases. One month earlier, five case of Pneumocystis
carinii pneumonia had been reported by Dr. Michael
Gottlieb in Los Angeles (CDC, 1981a).
• Tom Bethell is Washington correspondent of The American
Spectator. He wrote this article while he was a Media Fellow at the
Hoover Institution, Stanford University. An abbreviated version of
this article was published in SPIN. November, 1994.
315
'The patients did not know each other and had
no known common contacts or knowledge of sexual
partners who had had similar diseases', Dr. Gottlieb
reported. 'The 5 did not have comparable histories of
sexually transmitted disease ... Two of the 5 report-
ed having frequent homosexual contacts with various
partners. All 5 reported using inhalant drugs .. .' .
One month later, on July 3, 1981, there was a
second report in the CDC's Morbidity and Mortality
Weekly Report (CDC, 1981b). By now there were 15
cases of pneumocystis, and 26 cases of Kaposi's sarco-
ma were added to the list. The report pointed out that
KS was normally very rare, found among elderly men
and usually manifesting a 'chronic clinical course'. In
these new cases the 'fulminant clinical course' seemed
quite different. 'The occurrence of this number of KS
cases during a 30-month period among young homo-
sexual men is considered highly unusual', the report
added. This time there was no mention of drug use.
On the same day, however, there was an article by
Lawrence K. Altman in the New York Times (Altman,
1981). Headlined 'Rare Cancer Seen in 41 Homosex-
uals', this was probably the first article to appear in
the national press about the condition that would lat-
er be called AIDS. The 41 cases had been found in
New York and California. 'The cause of the outbreak
is unknown, and there is as yet no evidence of conta-
gion', Altman wrote. As before, none of the patients
knew one another, and Dr. James Curran, at that point
a 'spokesman' for the CDC, was reported as saying
that 'the best evidence against contagion is that no cas-
es have been reported to date outside the homosexual
community or in women' .
Dr. Alvin Friedman-Kien of New York University
Medical Center, who had reported many of these cases,
told Altman that among nine of the 'victims' (a word
that would later be abolished from AIDS reporting), he
had found 'severe defects in their immunological sys-
terns', with their T- and B-celllymphocytes evidently
316
malfunctioning. Most of these cases involved men who
had had 'multiple and frequent sexual encounters with
different partners', sometimes 'as many as ten sex-
ual encounters each night up to four times a week'.
And Altman added this little detail: 'Many' of these
men 'reported that they had used drugs, such as amyl
nitrite .. .'. Six weeks later, another report in MMWR
once again failed to say anything about drug use (CDC,
1981c).
At the CDC, Dr. James Curran was put in charge
of setting up a task force to investigate this new med-
ical phenomenon, which early on was named GRID
(Gay-related Immune Deficiency). On his second day
on the job, Harry Haverkos was signed up - it may
have helped that he and Curran had both gone to
Notre Dame. The newly formed group was called the
Kaposi's Sarcoma and Opportunistic Infections Task
Force, and it included a dozen or so members. One of
the first points to emerge was that virtually all the men
in the initial cluster of cases they investigated had been
frequent users of the nitrite inhalants called 'poppers'.
Nitrites have a respectable medical pedigree. In 1867,
amyl nitrite was used to relieve angina pains in heart
patients (Brunton, 1867). A volatile liquid, it came in a
mesh-covered glass ampule which could be broken, or
'popped' , and held to the nose. When the fumes were
inhaled, the pain subsided. Nitrites expand arteries, and
they do so by permitting muscles to relax (Nickerson,
1975). No reports of KS or immune problems surfaced
in those heart patients, but then the inhalant was used
only rarely, and during the patients' later years. There
are amyl-, butyl-, alkyl- and isopropryl nitrites, but it
is always the nitrite part that is important.
Early-warning signs about the recreational use of
nitrites began to appear in the medical literature in
the 1970s. Dr. Guy Everett of the Chicago Medi-
cal School noted in 1972 that amyl nitrite 'is widely
used by men, who most commonly sniff an inhaler
or break a 'popper' shortly before orgasm'. The pur-
pose seemed to be 'a sense of prolonged orgasm and
increased sense of excitement', he wrote. Some said
that poppers gave them a headache or aching eyes,
however, and 'these are certainly warning signs of pos-
sible serious side effects' (Everett, 1972). Dr. David
Smith, the founder and medical director of the Haight-
Ashbury Free Medical Clinic, added that although pop-
pers were gaining popularity outside 'the drug culture
or the deviant subculture', there seemed to be 'less use
or interest by either heterosexual or lesbian women'
.(Smith,1972).
The American Journal of Psychiatry warned in
1978 that 'popping and snorting volatile nitrites' was
a 'current fad for getting high'. But research raised the
question whether 'repeated use of these products could
increase the risk of developing cancer'. The problem
was that 'inhaled nitrites could interact freely with
endogenous trivalent nitrogen compounds to produce
nitrosamines', some of which 'are known to be car-
cinogenic (Sigell, 1978). The following year the same
journal noted that nitrite-use had proliferated among
homosexuals. Their use was 'strongly related to a num-
berofunconventional, deviant sexual practices' , which
were not named (Goode & Troiden, 1979). Reviewing
the physiological effects of nitrites on the eve of the epi-
demic, Thomas Haley of the FDA warned once again
that if a certain metabolism occurred, nitrites would
produce nitrosamines, 'which are potent carcinogens'
(Haley, 1980).
The CDC Task Force set forth in 1981 in search of
the epidemic. In The Band Played On, Randy Shilts
detailed their exploits in San Francisco:
'Dr. Harold Jaffe [of the CDC] looked nervously
toward the barroom door. Even with a stiff summer
breeze, the air was redolent with something thickly
acrid, like a strange mixture of battery acid and
vegetable shortening. The Ambush looked as seedy
as Jaffe had heard, the kind of place where you feet
stick to the floor. It was also the source of the
poppers about which the gay men in San Francisco
couldn't rave enough. The Ambush's own brand of
poppers, sold directly in an upstairs leather shop,
didn't give you headaches, patients told Jaffe ...
[B ut] Jaffe didn't believe he would find the solution
in poppers ... Amyl nitrite had been around for a
century without killing anybody' (Shilts, 1987).
Most AIDS reporters have been less candid than Randy
Shilts, but he nonetheless remained silent about the real
attraction of poppers. In fact, it has rarely appeared in
print. 'He avoided the issue' , said Hank Wilson, a gay
activist in San Francisco, who founded the Committee
to Monitor Poppers in 1981. 'The great breaker of the
taboos had his own taboo on this issue'. Mr. Wilson
himself, who manages a single-room occupancy hotel
in San Francisco, was candid about poppers. 'They
relax your sphincter muscle, okay?' he said. 'If you're
having casual sex, in a park or a bathroom or in a
tearoom, wherever, and it's quick, it's casual? You
don't generally have as much foreplay, you're more

orgasmic oriented, as opposed to pleasuring someone.
You see what I'm saying. Poppers facilitate quick anal
intercourse' (Wilson, 1993).
The same claim was published in Medical Aspects
of Human Sexuality, in 1975. Poppers were by the
mid 1970s being widely used by gay men, the jour-
nal reported, because they enabled 'the passive part-
ner in anal intercourse to relax the anal musculature
and thereby facilitate the introduction of the penis'
(Labataille, 1975).
Virtually all the early homosexual patients lat-
er diagnosed with AIDS had used poppers. 'Amyl
nitrite was used at least once by all the patients with
Kaposi's sarcoma (in their study)" Michael Marmor et
al. reported in The Lancet in 1982, 'and further pas-
sive exposure at homosexual discotheques was report-
ed by many' (Marmor et al., 1982). Analysing the data
from three early CDC studies, Dr. Haverkos and co-
workers found that out of 87 patients with Kaposi's,
pneumocystis or both, all but three had used poppers
(Haverkos et al., 1985). He had interviewed one of
those three himself, in a New York hospital. 'He had
pneumocystis, was short of breath, and was eager to
get back upstairs to his room' , Haverkos recalled. 'He
simply answered, 'no' to questions and skipped whole
sections of the interview' (Haverkos, 1994). Questions
about nitrite-use came at the end of the form. It is quite
likely, in fact, that all 87 of the men had used pop-
pers.
Surrounded by stacks of papers and medical jour-
nals in his cramped office, Haverkos gives several
reasons for suspecting that nitrites are the cause of
Kaposi's. The statistical connection between the two
is impressive. Repeated use of poppers, and the inci-
dence of KS, have been overwhelmingly confined to
gay men. 'About 96% of Kaposi's cases occur in gay
men, as opposed to 65% of all AIDS cases', he said.
Twice as many whites as blacks use poppers - and twice
as many get Kaposi's. After warnings about nitrites
spread through the gay community in the mid 1980s,
both the use of poppers and the incidence of Kaposi's
declined.
The unwritten rule of public health seems to be
that infectious disease must always trump toxicology,
even when the epidemiological indicators of infectious
disease are missing. 'If somebody could find me five
white women with Kaposi's who did not use nitrites,
between the ages of18 and 45, sexually linked to a man
with Kaposi's - just five couples - that would take me
back', Haverkos said. 'But we're 13 years into this
epidemic, and I have not seen such cases reported. If
317
this was a sexually transmitted agent, there ought to be
a handful of women like that' .
When asked what changes in AIDS research and
reporting he would like to see, he made a simple
request. About 5000 new cases of Kaposi's are reported
every year, but we still don't know how many of these
people used nitrites. Why not? The forms that clini-
cians fill out to this day lack questions about nitrite use.
They ask about sexual orientation, about intravenous
drug use and other categories traditionally linked to
AIDS. But nothing about poppers. 'I almost had a
question about nitrites put on the CDC surveillance
form back in 1984', Haverkos said. 'But they had to
weed it, make it a little shorter, and that was one of the
questions that they took off' .
No cases of KS have been reported among blood-
transfusion recipients where the donor himself later
developed the cancer. This suggests that HIV alone is
insufficient to cause the disease, and that whatever does
cause KS is not readily transmitted through blood. In
addition, a number ofHIV-free cases of KS have been
reported by two doctors, Alvin Friedman-Kien in New
York and Marcus Conant in San Francisco (Friedman-
Kien et al., 1990; Perlman, 1993).
Dr. Conant, Clinical Professor of Dermatology at
the University of California, San Francisco, told the
San Francisco Chronicle that he had found half a dozen
non-HIV cases of KS in the Bay Area, that 'dozens
more' have been found elsewhere in the country, and
that the evidence is 'overwhelming that [KS] is not
caused by HIV'. Dr. Conant rejects the nitrite theory
of KS as well, although he admitted that he has made
'no formal study' on the use of nitrites by his own KS
patients (Conant, 1994).
Kaposi's is a blood-vessel tumor, and nitrites act on
blood vessels. 'The lesions are most common on the
face, nose and chest', Haverkos said. 'If you're inhal-
ing vapors, that is where you will encounter the highest
concentrations'. Dr. Sidney Mirvish of the Universi-
ty of Nebraska Medical Center has demonstrated that
isobutyl nitrite vapor is mutagenic in the Ames test,
and that inhaled vapor is eleven times more dangerous
than nitrite in liquid form (Mirvish et aI., 1993).
'The primary action of nitrites is cell intoxication' ,
said Dr. Peter Duesberg, a cell biologist at the Universi-
ty of California, Berkeley. 'Nitrites reach into the bone
marrow and interfere with the creation of new blood
cells, including T-cells. They kill enzymes, and they
mutate DNA' (Duesberg, 1994a). Duesberg believes
that nitrite use alone is sufficient to explain most of
318
the early AIDS cases among gay men, where either
immune suppression or KS was found.
'Put all those points together', Dr. Haverkos said,
'and you don't have to be a rocket scientist to see that
there is some logic to the hypothesis'. Unfortunately
for the hypothesis, he added, 'the CDC and the NIH
then published two big studies in which they didn't
find an association between nitrites and KS'. Perhaps
the most important was the Multicenter AIDS Cohort
Study. Between 1984 and 1985, about 5000 gay men
in four cities participated. Those who developed AIDS
were compared with HIV-positive controls who did
not, and nitrite users did not seem to be concentrated
in the AIDS group. The authors, however, noted the
limitations of their own research. 'We did not attempt
to quantify nitrite usage ... It is thus possible that we
missed or obscured a meaningful association' (Polk et
al. 1987).
Patients were asked how frequently they had 'used
poppers during sex in the past two years', Haverkos
points out, and by the time subjects were asked the
question, many gay men had become wary of poppers
through point-of-sale warnings in gay bars and porn
shops. These had had their deterrent effect. Statis-
tics from the San Francisco Health Department show
a dramatic drop in the use of poppers between 1982
and 1988 (Wilson, 1994a). Therefore, by the time sub-
jects in the MAC study were interviewed, it is likely
than many were no longer using poppers, or had giv-
en them up two years earlier. The yes/no, ever/never
questions that have also been used in other epidemio-
logical studies have consistently failed even to try to
quantify lifetime use of nitrites.
In retrospect, it seems possible that government
medicine was not terribly interested in finding a toxi-
cological or behavioral cause of AIDS. The virologists
were on the case very quickly. The first three reports
in MMWR all include 'editorial notes' mentioning
cytomegalovirus, and such comments as: 'activation of
oncogenic virus during periods of immunosuppression
may result in the development of KS' (CDC, 1981b).
James Curran of the CDC considered the possibility
that a 'bad batch of the inhalants could have triggered
the immune problems'. That would explain why sick-
ness seemed to be limited to three cities. 'Contaminat-
ed vials' therefore might be the answer. But, Randy
Shilts reported, Curran never really gave credence to
the nitrite theory. After all, 'some five million doses of
nitrite inhalants were sold in American in 1980 alone'
(Shilts, 1987).
Mary Guinan, another Task Force member, thought
that 'somebody who gets a rush from heroin isn't going
to toy around with something as lightweight as dis-
co inhalants', an odd remark in view of their known
widespread use by homosexuals at that time (ibid).
Harold Jaffe ofthe CDC 'didn't believe he would find
the solution in poppers', Shilts reported. 'If the puzzle
was that simple, somebody would have solved it by
now' (ibid). In fact, amyl nitrite 'had been around for
a century without killing anybody'.
In Sentinel for Health, a history of the CDC pub-
lished in 1992, Elizabeth Etheridge describes the visit
of Jaffe and Guinan to San Francisco in 1981, where
they took blood samples from patients and controls, the
latter drawn from the practices of private physicians,
friends (but not sexual partners) of patients, and homo-
sexuals selected from VD clinics. Etheridge's report-
ing, based on an interview with Harold Jaffe, continued
as follows:
'When the task was done and the data from all the
cities were analyzed, there was little doubt it was a sex-
ually transmitted disease. The lifestyles of the patients
and the controls were quite different, the patients being
much more sexually active, much more likely to have
sex with people they did not know. Reports from the
lab showed that cases had much lower T-lymphocyte
counts than controls. While many of the patients were
routine users of amyl nitrites or 'poppers', no one in
the KSOI Task Force believed that the disease was a
toxicological problem' (Etheridge, 1992).
Haverkos was on the Task Force, and he still does
believe just that. Today Harold Jaffe is the director
of the di vision of HIV/AIDs at the Centers for Disease
Control and Prevention. He has relented a little, but not
much. 'The observation we're trying to explain is: Why
is it that among all persons with HIV infection, KS is
so common among gay men?' he said in an interview.
'And we don't know the answer to that. There are a
number of theories. It's at least possible that nitrites
might playa role in Kaposi's developing in gay men.
But I don't think they could be the entire explanation,
because Kaposi's does occur in other HIV infected
persons who do not use nitrites' (Jaffe, 1994).
Haverkos replied that these cases are extremely
rare, and he says that there has been no follow-up to
determine if misdiagnosis occurred. 'I don't think you
can dismiss nitrites because of a few underevaluated
studies', he said (Haverkos, 1994).
'The difficulty is this', Dr. Jaffe added. 'Nitrite use
among gay men also tends to be associated with other
behaviors. Men with a heavy use of nitrite inhalants

often also are highly sexually active, and have other
sexually transmitted diseases. So it's very hard in doing
studies to be able to separate out all these behaviors that
are highly associated' .
Nonetheless, it seems remarkable that professional
disease sleuths should have found it so hard to believe
that a carcinogen, reported as a new fad among homo-
sexual men in the 1970s, might be the cause of a new
cancer that emerged in the 1980s - and emerged among
the very people who had been inhaling it.
An indicator of the CDC's evident desire to sub-
ordinate toxicity to infection in searching for a cause
came in 1983. In that year, even before HIV was iden-
tified as 'the virus that causes AIDS', the Public Health
Service put out a brochure ('What Gay and Bisexual
Men Should Know About AIDS') specifically claiming
that nitrite inhalants had been 'ruled out' as a cause of
AIDS. 'Current research favors the theory that AIDS is
caused by an infective agent, possibly a member of the
retrovirus group', the pamphlet explained (U.S. Public
Health Service, 1983).
The second most important experiment enabling
the CDC to 'rule out' poppers was a study done on
mice, conducted in 1982-83 by Daniel Lewis and Den-
nis Lynch of the National Institute of Occupational
Safety and Health (a subdivision of the Centers for
Disease Control). Mice were exposed to various con-
centrations of isobutyl nitrite for up to 18 weeks, and
the effect on their immune systems was measured. A
sharply lower white blood cell count was observed in
male mice (down to nearly one third the level of con-
trols), but the overall conclusion of the study was that
'at the levels tested, isobutyl nitrite had no signifi-
cant detrimental effect on the immune system of mice'
(Haverkos & Dougherty, 1988).
In May, 1994, however, the National Institutes
of Health sponsored a 'technical review' of nitrite
inhalants at a public meeting in Gaithersburg, Mary-
land. Among the speakers was Daniel Lewis. In con-
ducting the experiment, he explained, nitrite dosage
had been kept low, approximating the background-
exposure levels encountered by humans working in a
poppers factor. In a detailed report on the meeting, the
writer John Lauritsen noted: 'Lewis explained that in
determining the dose, they had to adjust it below the
level at which they were 'losing' the mice'. It is pos-
sible that the mice they 'lost' had in fact succumbed
to immunotoxicity - exactly what the study claimed
not to have found (Lauritsen, 1994a). When asked
how he accounted for the discrepancy between the
findings of this study, and others definitely showing
319
immune-system impairment (Ortiz & Rivera, 1988),
Lewis responded: 'dosage and length of exposure'.
Nitrites 'should be considered a hazardous substance' ,
he added (Lauritsen, 1994b).
What about the testing of nitrites on human sub-
jects? Eighteen male volunteers were tested for a few
days by Elizabeth Dax and William Adler at the Addic-
tion Research Center in the late 1980s. After the last
inhalation, blood was drawn for the immune profile;
and then again after one, four and seven days had
passed. Modest depression of T-Iymphocyte counts
and natural killer cells were observed, with a rebound
to baseline levels taking place several days after the
last inhalation (Dax, 1991). Lee Soderberg of the
University of Arkansas also made a presentation at
the Gaithersburg session. His experiments, with mice
subjected to a stronger nitrite dose, definitely showed
immune-system impairment, especially a reduction of
macrophage activity. Here, too, immune functions
seemed to recover after about a week (Soderberg &
Barnet, 1991).
During a question period, Dr. Duesberg, who was
an observer although not a speaker at the session, raised
this issue of reversibility. Among homosexuals, he
pointed out, nitrite use had often gone on for years.
What is needed, he suggested, are longer-term studies.
But Soderberg said that his team had 'no data on more
chronic exposure' (Lauritsen, 1994a).
Duesberg said later that those who had so care-
fully investigated smoking and lung cancer would not
have been content to give subjects a few cartons of
Marlboros, and having found that they caused no ill
effects, proclaim cigarettes to be safe. 'With drugs, the
dose is the poison', he said (Duesberg, 1994a). And
the dose accumulates. The apparent failure to appre-
ciate this point is the answer to Jaffe's and Curran's
earlier belief that nitrites could hardly be the cause of
disease, because nitrite-use was already so widespread
by 1981. The key point is that nitrite-use as a fad or
habit in the gay community had apparently been going
on for about ten years by the time Kaposi's emerged.
And that may well be the time it takes for the critical
dose-level to build up.
Duesberg has proposed to correct the research lacu-
na by exposing mice to nitrites for longer periods, and
then seeing what happens. Will they develop pneumo-
cystis or something resembling Kaposi's? In August,
1993, while he was working on a grant application
to fund such an experiment (together with an experi-
enced animal researcher from the University of Cali-
fornia, Davis), Duesberg discussed the situation with
320
Daniel Koshland, who at the time was both the edi-
tor of Science magazine and, like Duesberg, a mem-
ber of the Department of Molecular and Cell Biology
at U.C. Berkeley. Duesberg told Koshland about the
widespread use of poppers among homosexuals, the
toxicity of nitrites, and the need for further animal
experimentation. Koshland had heard very little about
all of this potentially crucial background to the AIDS
controversy (Duesberg, 1994a). The upshot was that
he supported Duesberg's grant proposal. His letter of
support was submitted along with the grant applica-
tion to the National Institute on Drug Abuse. In it he
wrote:
'As an observer, I have in the past been critical of
Duesberg for not suggesting experiments to resolve
this controversy. However, he has now answered
my call with a proposal to test the role of nitrite
inhalants as a co-factor in AIDS. Certainly this
idea seems intuitively to have merit, as nitrites
have long been known for their potent mutagenic
and carcinogenic effects. He plans to extend some
unfinished work by other laboratories in the mid-
1980s on mice .. .' (Koshland, 1993).
Despite this endorsement from the editor of the
leading science journal in the country, the proposal
was turned down by the National Institute on Drug
Abuse. The agency cited Duesberg's lack of 'prelimi-
nary experiments' in the field, and his failure to give
a full hearing to opposing views. He resubmitted an
amended proposal in August 1994, again supported by
an endorsement from Daniel Koshland. But this too
was turned down, in a letter dated November 30, 1994.
'No further consideration be given to this application',
the accompanying note read (Duesberg, 1994b).
Butyl nitrites were officially banned by the Anti-
Drug Abuse Act of 1988 (Public Law 100-690), but
manufacturers responded by selling chemical variants
as 'room odorizers' and marketing them under such
names as 'Rush', 'Ram', and 'Locker Room'. Then,
in the 1990 Omnibus Crime Control Act, mainly in
response to the concerns of Rep. Mel Levine of Cali-
fornia, Congress outlawed the manufacture and sale of
all alkyl nitrites. Once again the chemistry was recon-
figured, and by 1992 nitrites were back on the market,
sold as video head cleaner, polish remover ('Just like
the old daze!' ad copy in a gay magazine trumpet-
ed), carburetor cleaner ('The good stuff') and leather
stripper ('Not an overpriced 'headache in a bottle' like
those other brands') (Wilson, 1994b).
'The use of poppers is increasing across the board
in the big cities' , the anti -poppers activist Hank Wilson
claimed, in an interview in the summer of 1994. 'It's in
the air in the San Francisco clubs. I personally stopped
going to the sex clubs about 18 months ago because
the air got so bad' (Wilson, 1994c).
Wilson's boyfriend, who always used poppers with
sex and had KS, died last year of AIDS. Wilson himself
was diagnosed with AIDS in 1987, but looks to be
in good health (he steers clear of AZT). Institutional
memory in the gay community is short, Wilson said,
and there is concern that young men who have come
to the big city in the 1990s will think of poppers as
the 'new toy'. They know little of the battles that were
fought a decade ago, when point-of-sale warnings were
mandated in California, but have since lapsed.
Wilson was furious that James Curran, now in a
position of real power as the chief of AIDS research
at the CDC, had not issued a community alert. Wil-
son cited a number of recent studies, including a 1994
report published in the Journal of the American Med-
ical Association (Lemp et at., 1994), showing incon-
trovertibly that popper use is a risk factor for unsafe
sex. (A call by this reporter to Curran's office at the
CDC was referred to the press office. Tom Skinner of
that office said: 'It's my understanding that the use of
nitrites is associated with unsafe sex. But to say that it's
directly the cause of unsafe sex, there is no scientific
proof of that'). (CDC, 1994).
Wilson's group is affiliated with ACT UP/Golden
Gate, and by the end of 1993 a few of its members
began to take action. Ernest Harding of Los Angeles
wrote to Kristine Gebbie's office complaining about
a letter from the Consumer Product Safety Commis-
sion, reassuring one of the poppers manufacturers that
their nitrite configuration was not covered by the law
and was therefore legal. At the same time, Shane Que
Hee, an associate professor of Environmental Health
Sciences at UCLA, who has written a textbook on bio-
logical monitoring with a chapter devoted to volatile
nitrites, wrote to Rep. Henry Waxman (D-Calif) rec-
ommending that 'the immunosuppressive properties
of these drugs should be researched completely before
they are sold publicly' (Hee, 1993).
The professor also wrote to the Consumer Product
Safety Commission in Washington, urging that it with-
draw approval of nitrite inhalants. He received a reply
from the Office of Compliance and Enforcement saying
that the commission had no such authority. 'The nitrite
ban enacted by Congress is not all inclusive' , Michael
Bogumill wrote, 'as it is limited to consumer prod-

ucts containing volatile alkyl nitrites, which, accord-
ing to chemical experts, does not necessarily include all
volatile organic nitrites' (Bogumill, 1994). Therefore
the commission could do nothing. Nitrites continue to
be sold, in compliance with the letter but not the spirit
of the law.
In the correspondence with Gebbie, Ernest Hard-
ing added that the alcohol congener in poppers is not
the relevant issue. 'It is the nitrite component that is
dangerous, and on this basis we cannot permit the
sale of any such product, whether it be disguised as a
room odorizer, video-head cleaner, or any other obfus-
cation'. Gebbie responded by asking NIH if some-
thing couldn't be done, and in response the 'technical
review' of nitrite inhalants was held in Gaithersburg in
May.
One session was titled, 'Do Nitrites Act as a Co-
Factor in Kaposi's Sarcoma?' The best known speak-
er was the National Cancer Institute's Robert Gal-
lo, co-discoverer of HIV. What he said was note-
worthy. Although HIV was surely a 'catalytic factor'
in Kaposi's, he said, 'there must be something else
involved'. Then he added:
'I don't know if I made this point clear, but I think
that everybody here knows - we never found HIV
DNA in tumor cells of KS. So this is not directly
transforming. And in fact we've never found HIV
DNA in T cells, although we've only looked at a
few. So in other words we've never seen the role of
HIV as a transforming virus in any way. The role
of HIV has to be indirect' (Lauritsen, 1994a).
In response to a question from Dr. Haverkos, who
said that not a single case of KS had been reported
among blood recipients where the donor had KS, Gal-
lo allowed: 'The nitrites could be the primary factor'.
Also worth noting is a comment of Anthony Fauci, at
the time chief of AIDS research at NIH. In a San Fran-
cisco Chronicle article questioning the link between
mv and Kaposi's, Fauci was quoted as saying: 'I
would not be totally surprised if we found out that
KS is caused by a combination of things. Maybe by
an agent that is at this point unrecognized' (Perlman,
1993).
Let us briefly review: In 1981, the CDC found that gay
men were coming down with unusual diseases, among
them a rare cancer, Kaposi's sarcoma. It turned out
that with very rare exceptions, all these men had been
inhaling a volatile substance of known mutagenic and
321
carcinogenic potential, for the purpose of getting 'high'
and facilitating anal intercourse. Despite the best reg-
ulatory efforts of Congress, this substance is still sold
legally. Meanwhile in 1984, in the course of an elec-
tion campaign, we were told that the cause of AIDS
had been discovered. The virus HIV was the culprit.
Ten years later, we were told by the co-discoverer of
the virus that nitrite inhalants 'could be the primary
factor' in KS, which, Dr. Fauci thought at the end of
1993, might be caused 'by an agent that at this point
is unrecognized'. By mid 1994, then, it was clear from
the mouths of the government's leading researchers
that they still did not understand AIDS.
That August, Haverkos attended the 10th Inter-
national AIDS Conference in Yokohama. He wasn't
well-known enough to give a speech, but he was given
space to displayed the 'poster' that he and the CDC's
Peter Drotrnan had put together. It analyses 12 epi-
demiological studies that have been used to examine
the role of nitrites and other potential co-factors in
the development of Kaposi's, and it shows that these
questionnaires had failed to quantitate nitrite use.
'Went okay', Haverkos said later, in his usual low-
key manner. Nothing earth-shattering. A few people
came by and talked. A reporter from a Canadian news-
paper interviewed him. 'I've been figuring this story
was going to break since, oh, about 1985', he said with
a laugh.
Then, near the end of 1994, there was an unex-
pected development in the story. In mid-December, a
husband and wife team at Columbia University held a
press conference declaring that they had found traces
of what may be a newly detected virus in tissue tak-
en from deceased AIDS patients with Kaposi's. The
scientists, Yuan Chang and Patrick S. Moore, used
a new technique (representational difference analysis)
to help identify molecular fragments from genes of the
apparent virus. The DNA sequences were homologous
to, but distinct from protein genes of the herpes virus.
They were found in 90% of KS-tissue from patients
who had died with AIDS-related KS, in 15% of non-
KS tissue from AIDS patients, and not at all in non-KS
tissue from people without AIDS.
With accompanying news media fanfare, their find-
ings were reported in Science magazine (Chang et
al., 1994). Earlier that year, Moore had attended
Haverkos's nitrite review session as a silent observer.
Before joining his wife at Columbia, he had worked
for the Centers for Disease Control and Prevention in
Colorado, and for New York City's public health ser-
vice.
322
Moore and Chang duly emphasized the prelimi-
nary nature of their findings. They had neither isolat-
ed the virus, nor determined its complete structure,
nor proved that it was the cause of Kaposi's sarcoma.
'There's a long step between finding DNA sequences
and having a virus', said Dr. George Miller, a Yale
University expert in herpes viruses (Altman, 1994).
Nonetheless, Dr. Harold Jaffe of CDC told Jon Cohen
for an accompanying article in Science that 'it's a
tremendously exciting result ... At this point we can't
say that it's the etiologic agent, but I think it's a very
good candidate' .
The opinion of Dr. Gallo was sought. The new
paper was 'really good work' , he said, but he still had
'major questions' (Cohen, 1994). These dealt with the
claim that the putative virus is found rarely or not at all
outside the population of gay men. (This would make
it unique among herpes viruses, which are found in a
large proportion of the general popUlation.) Cohen's
Science article was headlined: 'Is a New Virus the
Cause of KST
Almost in passing, the main Science paper not-
ed that investigators had long suspected that AIDS-
related Kaposi's might be infectious, and that over
the years suspected causal agents had included:
cytomegalovirus, hepatitis B virus, human herpes virus
6, HIV, and Mycoplasma penetrans. 'Extensive inves-
tigations, however, have not demonstrated an etiologic
association between any of these agents and AIDS-
KS', Chang, Moore et al. added. Thus, it seemed, HIV
was quietly dropped from the list of the possible causes
of Kaposi's.
Lawrence K. Altman, who attended the press con-
ference, came through with a front-page story in the
New York Times (Altman, 1994). Headlined 'Appar-
ent Virus May Be a Cause of Fatal Cancer in AIDS
Patients', it made no mention of HIV at all. A simul-
taneous report by Lisa M. Krieger in the San Francis-
co Examiner (,AIDS-related cancer linked to herpes
virus') began as follows:
'New research suggests that Kaposi's sarcoma,
a potentially deadly disease long thought to be
caused by HIV, is instead caused by a type of sex-
ually transmitted herpes virus that preys on people
with AIDS' (Krieger, 1994).
Four days later, a second story by Altman was pub-
lished in the New York Times (Altman, 1994b). Since
its initial article in July, 1981, the paper had remained
loyal to the infectious-agent theory of Kaposi's and
said very little about nitrite use. In this second article,
however, Altman raised a number of interesting ques-
tions. If the new 'virus' causes Kaposi's, for example,
'why did it appear at the same time as HIV?' Why two
new viruses at once? And 'does the Kaposi's sarco-
ma virus suppress the immune system independently
of the AIDS virusT He further asked: 'Why has the
percentage of AIDS patients with Kaposi's sarcoma
declined in the United States over the last ten years?'
(Nitrite use, of course, has likewise declined.) Altman
still seemed to be skirting the key question: What role,
if any, was reserved for HIV in the development of
Kaposi's?
When I spoke to Dr. Harry Haverkos in mid-
December, he still had not seen the article in Science,
but he had discussed the news with former colleagues
at the Centers for Disease Control in Atlanta. If the
new discovery held up, he said, and the etiologic agent
for KS had indeed been found, HIV would probably
still be regarded as a co-factor predisposing the patient
to KS by weakening the immune system. He used the
analogy of tuberculosis. About ten million people in
the U.S. are infected with TB, he said, but only about
one million will develop active disease in their life-
time. Various factors (coal-miners' disease, for exam-
ple) may weaken the TB-infected patient sufficiently
to allow the dormant bacillus to become active.
Haverkos stressed, however, that the Columbia
University team still had a way to go. Just as earli-
er sexually transmitted agents for KS had not survived
closer examination, so this new (presumed) virus might
not either. Meanwhile, he admitted, his nitrite hypothe-
sis had been dealt a setback, if only because researchers
would not take it seriously 'until they have sorted out
this new factor.' Which could take time. In the mid-
1980s, he recalled, he was about to embark on a study
of nitrites with the military, when just at that moment
the Armed Forces Institute of Pathology, on the cam-
pus of Walter Reed Hospital in Bethesda, came forth
with the hypothesis that mycoplasmas were a co-factor
for KS. This theory didn't survive scrutiny, but 'by the
time they sorted it out, the impetus to do the study I
had proposed had withered away, and the people at the
Institute who were interested in it had been transferred
somewhere else.'
Still, he said, there was a positive side to the new
development. 'It does suggest that there must indeed
be a co-factor for KS.' Back in 1984, when the cause
of AIDS was announced at a press conference held by
the HHS Secretary Margaret Heckler, it was assumed
that the then culprit, HIV, was the necessary and suf-
ficient cause of a syndrome that prominently included

Kaposi's sarcoma. Ten years later, the unwary read-
er might not have noticed that a certain three-letter
acronym was totally absent from the press release dis-
tributed at the Moore and Chang news conference at
Columbia University. HIV had quietly disappeared
from the picture.
References
Altman, L.K., 1981. Rare Cancer Seen in 41 Homosexuals. New
York Times, July 3.
Altman, L.K., 1994a. Apparent Virus May Be a Cause of Fatal
Cancer in AIDS Patients. New York Times, December 16, p. I.
Altman, L.K., 1994b. Going off the beaten path to track down clues
about AIDS. New York Times, December 16, p. 1.
Bogumill, M., 1994. Letter to Prof. Hee, Feb 14.
Brunton, T.L., 1867. On the use of nitrite of amyl in angina pectoris.
Lancet ii: 97-98.
CDC, 1981a. Pneumocystis pneumonia - Los Angeles. MMWR
1981; 30: 250.
CDC, 1981b. Kaposi's Sarcoma and Pneumocystis Among Homo-
sexual Men - New York City and California. MMWR; 30: 305.
CDC, 1981c. MMWR, 30: 409--410; Aug 28,1981.
CDC, 1994. Author's interview with Skinner, August 1994.
Chang, Y., E. Cesarman, M.S. Pessin, P. Lee, J. Culpepper, D.M.
Knowles & P.S. Moore, 1994. Identification of Herpesvirus-
Like DNA Sequences in AIDS-Associated Kaposi's Sarcoma.
Science 266: 1865-1869.
Cohen, J., 1994. Is a New Virus the Cause of KS? Science 266:
1803-4.
Conant, M., 1994. (no formal study) faxed communication to author,
August.
Dax, E.M., W.H. Adler, J.E. Nagel, W.R Lange & J.H. Jaffe, 1991.
Immunopharmocologyand Immunotoxicology 13: 577-587.
Duesberg, P., 1994a. Author's interview, August.
Duesberg, P., 1994b. Personal communication, December.
Etheridge, B.W., 1992. Sentinel for Health. Univ of Calif., Berkeley,
p326.
Everett, G.M., 1972. Effects of Amyl Nitrite ('Poppers') on Sex-
ual Experience. Medical Aspects of Human Sexuality 6: 146.
Friedman-Kien, A.E., B.R. Saltzan, Y. Cao, M.S. Nestor, M.
Mirabile, lJ. Li & TA Peterman, 1990. Kaposi's sarcoma in
HIV-negative homosexual men. The Lancet 335: 168-169.
Goode, E. & R. Troiden, 1979. Amyl Nitrite Use Among Homosex-
ual Men. Am. J. Psychiatry 136: 8.
Haley, T.J., 1980. Review of the physiologica1effects of amyl, butyl
and isobutyl nitrites. Clinical Toxicology 16: 317-329.
Haverkos, H.W., P. Pinsky, P. Drotman & D.J. Bregman, 1985.
Disease Manifestation among Homosexual Men with Acquired
Immunodeficiency Syndrome: A Possible Role of Nitrites in
Kaposi's Sarcoma. Sexually Transmitted Diseases 12: 4.
323
Haverkos, H.W. & J.A. Dougherty, 1988. Health Hazards of Nitrite
Inhalants. NIDA Research Monograph 83, 50-59.
Haverkos, H.W., 1994. This and other quotations, from author's
several interviews with Haverkos in 1994.
Hee, S.Q., 1993. Letter to Rep. Waxman, Dec 10.
Jaffe, H., 1994. Author's telephone interview, August.
Koshland, D., 1993. In Duesberg's research proposal to NIDA, 'Ani-
mal tests of the AIDS risks of nitrite inhalants', Aug 27.
Krieger, L.M., 1994. AIDS-related Cancer linked to Herpes Virus.
San Francisco Examiner, December 16, p. A-I.
Labataille, L., 1975. Amyl Nitrite employed in homosexual rela-
tions. Med. Aspects Human Sexuality 9: 122.
Lauritsen, J., I 994a. The Poppers - KS Connection. New York
Native, June 13.
Lauritsen, J., 1994b. NIH reconsiders nitrites' link to AIDS.
Biorrechnology 12: 762.
Lemp, G.F., A.M. Hirozawa, D. Givertz, G.N. Nieri, L. Anderson,
M.L. Lindegren, R.S. Janssen & M. Katz, 1994. Seroprevalence
of HIV and Risk Behaviors Among Young Homosexual and
Bisexual Men. JAMA, 449-454.
Marmor, M., A.E. Friedman-Kien, L. Laubenstein, RD.
Bryum, D.C. William, S. D'Onofrio & N. Dubin, 1982. Risk
Factors for Kaposi's Sarcoma in Homosexual Men. The Lancet,
1086.
Mirvish, S., J. Williamson, D. Babcook & S. Chen, 1993. Muta-
genicity of Iso-Butyl Nitrite Vapor in the Ames Test and Some
Relevant Chemical Properties. Environmental and Molecular
Mutagenesis 21: 247-252.
Nickerson, M., 1975. Vasodilator drugs. In: The Pharmacologic
Basis of Therapeutics, 5th ed, N.Y. Macmillan; p 727-743.
Ortiz, J.S. & Y.L. Rivera, 1988. in Haverkos, 1988, pp. 59-73.
Perlman, D., 1993. New Doubts About Link Between HIV, Kaposi's.
San Francisco Chronicle, Dec 1 A3.
Polk, B.P., R Fox, R Brookmeyer, S. Kanchanaraksa, R. Kaslow,
B. Visscher, C. Rinaldo & J. Phair, 1987. Predictors of the
acquired immune deficiency syndrome developing in a cohort
of seropositive homosexual men. N. Eng!. J. Med. 316: 62-6.
Shilts, R., 1987. And The Band Played On. St. Martin's Press, N.Y.
pp 86-87.
Sigell, L.T., F.T. Kapp, G.A. Fusaro, E.D. Nelson & RS. Falck,
1978. Popping and Snorting Volatile Nitrites: A Current Fad for
Getting High. Am. J. Psychiatry 135: 1216-1218.
Smith, D.E., 1972. Commentary. Med. Asp. Hum. Sex. 6: 151.
Soderberg, L. & J.B. Barnet, 1991. Exposure to inhaled isobutyl
nitrites reduces T-cell blastogenesis and antibody responsive-
ness. Fundam. Applied Toxico!. 17: 821-824.
U.S. public Health Service, 1983. What Gay and Bisexual Men
Should Know About AIDS (brochure). A copy was made avail-
able by Hank Wilson.
Wilson, H., 1993. Author's interview, December.
Wilson, H., 1994a. Prevalence of Popper Use, S.P. Hepatitis B-City
Clinic Cohort, unpublished report, S.P. AIDS office Dec 27,
1993, available from Hank Wilson.
Wilson, H., 1994b. Hank Wilson has collected and made available
ad copy from a wide variety of gay publications.
Wilson, H., 1994c. Author's interview, August.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 325-330, 1996.
© 1996 Kluwer Academic Publishers.
NIDA meeting calls for research into the poppers-Kaposi's sarcoma
connection
John Lauritsen
26 St. Mark's Place, New York, NY 10003, USA
When the first cases of AIDS, or the predecessor cases
of GRID (Gay Related Immune Deficiency) were iden-
tified in 1981, the nitrite inhalants known as 'poppers'
were high on the list of etiological suspects. Here was
a drug used heavily and almost exclusively by the peo-
ple getting sick: a subset of gay men. It was especially
plausible that the nitrites, as powerful mutagens, might
be responsible for Kaposi's sarcoma (KS), which was
then believed to be a rare form of cancer.
Independent studies conducted in the early 1980s
strengthened the poppers-KS hypothesis. However, the
Centers for Disease Control (CDC), after some per-
functory and misguided research - in particular, a
deeply flawed study on mice - claimed to find 'no
evidence of immunotoxicity'. The 1984 press confer-
ence, at which Secretary of Health Margaret Heckler
announced that the 'probable cause of AIDS has been
found' , nipped in the bud any further research on pop-
pers.
Now, a decade later, high-ranking members of the
Public Health Service are again taking seriously the
role of poppers in AIDS. The National Institute on Drug
Abuse (NIDA) sponsored a high-level meeting, 'Tech-
nical Review: Nitrite Inhalants' , held in Gaithersburg,
MD (outside Washington, DC) on the 23rd and 24th
of May, 1994. The toxicologists, AIDS researchers,
and others present reached a consensus urging research
into the connection between the nitrite inhalants (or
'poppers') and Kaposi's sarcoma (KS). The meeting
was organized by Harry Haverkos of NIDA, who has
written since 1985 about the health hazards of the
nitrite inhalants. (Haverkos et al., 1985; Haverkos &
Dougherty, 1988).
Robert Gallo, as the unofficial voice of the AIDS
Establishment, disclosed important revisions in the
AIDS-paradigm. The Number One AIDS Expert in
America shocked some of those present when he dis-
closed that HIV cannot cause KS by itself. He fur-
325
ther stated that HIV does not kill T-cells, and indeed
has never been found in them; whatever damage HIV
allegedly does, it does indirectly.
Also in attendance as an invited observer was
molecular biologist Peter Duesberg, the foremost crit-
ic of the HIV-AIDS hypothesis. He has designed
experiments, and is waiting for funding, to examine
the effects of long-term nitrite exposure in animals.
Though Duesberg has been much abused in both the
popular and the semi- scientific press, he was warmly
received by the other scientists at the meeting, who lis-
tened to him with respect when he discussed points of
retrovirology, on which he is one of the world's leading
authorities. A reconciliation took place between Robert
Gallo and Peter Duesberg; the two are on friendly terms
again, for the first time since 1987, when the first inter-
view with Duesberg appeared (Lauritsen, 1987).
Background: poppers and their toxicities
As a prescription drug, amyl nitrite was used by elder-
ly people for emergency relief of attacks of angina
pectoris (heart pain).
Historically, the use of nitrite inhalants (amyl
nitrite, butyl nitrite, isobutyl nitrite, etc.) for recre-
ational purposes has been limited almost entirely to gay
men. The first reports of recreational use date from the
early 1960s, after the amyl nitrite prescription require-
ment was eliminated by the FDA. The drug appeared to
intensify and prolong the sensation of orgasm. It facili-
tated anal intercourse by relaxing the smooth sphincter
muscles and deadening the sense of pain. (Lauritsen &
Wilson, 1986; Newell, Spitz, & Wilson, 1988; Laurit-
sen, 1993)
The FDA re-instated the prescription requirement
in 1969. In 1970 a new industry stepped into the breach,
marketing little bottles containing mixtures of butyl
and isobutyl nitrite. By 1974 the poppers craze was in
full swing. Ads for them appeared in all gay publica-
326
tions. At gay discotheques men could be seen, shuf-
fling around in a daze, holding poppers bottles under
their noses. The miasma of nitrite fumes was taken for
granted at gay gathering places: bars. baths, discos,
leather clubs. Some gay men were never without their
little bottle, from which they snorted fumes around the
clock (Lauritsen, 1993). Two separate studies in the
70s found that some gay men could no longer perform
sexually without the use of poppers (Wood, 1988).
The toxicities of the volatile nitrites were well
known before the advent of AIDS. In 1980 Thomas
Haley published a two-page summary of nitrite toxic-
ities, with 115 references listed.
Here are a few of the highlights:
The toxic effects of amyl nitrite inhalation include
rapid flushing of the face, pulsation in the head,
cyanosis, confusion, vertigo, motor unrest, weak-
ness, yellow vision, hypotension, soft thready pulse,
and fainting. Accidental prolonged inhalation of amyl
nitrite has resulted in death from respiratory failure ....
Fatalities have occurred in workers exposed to organ-
ic nitrates after strenuous exercise 1 to 2 days after
cessation of exposure. Nitrite causes a loss of tone of
the vascular bed and pooling and trapping of blood in
the veins of the lower extremities, resulting in marked
arteriolar constriction and the induction of anoxemia
in vital tissues, causing death .... The formation
of methemoglobin by aliphatic nitrite interferes with
oxhemoglobin, causing anoxia of vital organs .... The
use of volatile nitrites to enhance sexual performance
and pleasure can result in syncope and death by car-
diovascular collapse (Haley, 1980).
Also in 1980 appeared the first of several studies to
demonstrate that the volatile nitrites are powerfully
mutagenic (i.e. they cause cellular mutations) (Quinto,
1980). This is cause for concern, as almost all known
carcinogens are mutagens.
Subsequent studies, both in vitro and in vivo, have
shown that poppers damage the immune system. They
cause two kinds of anemia: Heinz body hemolytic
anemia and methemoglobinemia. They damage the
lungs. They have the potential to cause cancer by
producing deadly N-nitroso compounds in interaction
with many common drugs and chemicals, including
antihistamines, artificial sweeteners, and pain killers
(Haverkos & Dougherty, 1988).
Nevertheless, despite compelling epidemiological
and toxicological evidence, the Centers for Disease
Control (CDC) exonerated poppers, ostensibly for two
reasons: First, the CDC found AIDS patients who had
never used poppers; therefore, they argued, poppers
could not be the cause. (The CDC's assumption was
that 'AIDS' constituted a single, coherent disease enti-
ty with a single cause.) Second, the CDC conducted a
brief study of mice in 1982-1983, and claimed to find
'no evidence of immunotoxicity' (Centers for Disease
Control, 1983). The reasons for these negative findings
were explained at the Gaithersburg meeting by one of
the investigators, Daniel Lewis (see below).
The epidemiology of nitrite use
After a welcome by Richard A. Millstein, Deputy
Director of NIDA, Harry Haverkos opened the meet-
ing with a brief overview of the volatile nitrites, their
use and regulation. The meeting them turned to epi-
demiology.
For the most part, the epidemiologists viewed pop-
pers as a risk factor for AIDS because their use favors
transmission of HIV via unsafe sex. However, much of
their information strongly supports the hypothesis that
the mutagenic and carcinogenic nitrites function more
directly - as either sufficient cause of AIDS or at least
as a powerful co- factor with HIV infection.
For example, according to Jay Paul (UC San Fran-
cisco) the highest risk for AIDS (,Level 4') was the
use of poppers and four other drugs.
Lisa Jacobson (Johns Hopkins, Baltimore) reported
that 60-70% of the several thousand gay men at risk
for AIDS who participated in the Multicenter AIDS
Cohort Study had used nitrites. Data from the same
study showed that HIV-negatives had on average 25
months of use, HIV-positives 60 months, and AIDS
patients over 65 months - an apparent dose-response
relation. When asked whether there was even one gay
AIDS case in the cohort who had not used drugs, a
slightly disconcerted Jacobson replied, 'I have never
looked at the data in this way'.
Kenneth Mayer, a physician living in the Boston
area, was among the first to sound the warning about
poppers (Mayer & D'Eramo, 1984). He discussed sur-
veys, which found that the use of poppers is a risk factor
for becoming HIV- antibody-positive. But what does
that mean? He mentioned two possibilities: being HIV-
antibody-positive might be a marker for other health
risks, or it might be a marker for illness. He posed the
basic question: which is more hazardous, unsafe sex
or drug use?

The marketing of poppers
Hank: Wilson, a San Francisco activist who in 1981
founded the Committee to Monitor Poppers, spoke
on 'Advertising Trends'. He said that, with regard to
poppers, gay men had been 'uninformed, misinformed,
partially informed, and confused' . He then showed col-
or slides of several dozen poppers ads, from the early
70s through the late 80s. This must rank among the
most brilliant advertising campaigns in history. Within
only a few years hundreds of thousands of men were
persuaded that poppers were an integral part of their
own 'gay identity'. The ads conveyed the message
that masculinity and sex appeal were intimately linked
to the inhalation of noxious chemical fumes. Bulging
muscles were linked to a drug that is indisputably haz-
ardous to the health.
Beginning in the early 70s ads for poppers appeared
in all of the gay press - ads for special inhalers - an ad
for a brand named 'Discorama', specifically targeted
at disco dancers. One ad gave an 800 number, with the
message, 'We'll pay you to try ... .' (the free trial
tactic that has also been used on the street by dealers
of heroin, crack, and other such commodities). An ad
for the poppers brand RUSH focused on the phrase,
'Better Living Through Chemistry' - and no irony was
intended.
However, warnings about the dangers of poppers
began to appear in both the gay and the mainstream
press, and for the decade of the 80s, these messages
competed with disinformation from the poppers indus-
try and their allies. Wilson showed the front page of
a December 1981 issue of the New York Native, with
a banner headline, 'Do poppers cause cancer?' This
message got across even to people who just glanced at
it on the newsstand. A Pittsburgh paper, OUT, repeated
that same heading. The City of San Francisco required
that a warning notice be placed at all points of sale for
poppers. The June 4-17 1984 issue of the New York
Native carried an article, 'Poppers: The Writing On
The Wall'. On 19 July 1985, the Seattle Gay News
published a boxed warning on poppers. And in 1985
poppers were banned from the most popular disco in
San Francisco. The mainstream press in San Francis-
co also began to carry the message that poppers were
dangerous.
But the poppers industry had its own resources. A
1983 pamphlet published by the CDC, 'What gay and
bisexual men should know about AIDS' , claimed that
there was no relationship between AIDS and poppers,
on the basis of a single study done on mice (to be
327
discussed below). In effect, the government gave the
green light on poppers use. The CDC's study on mice
was cited in a press release sent out by Joseph F. Miller,
President of Great Lakes Products, the world's largest
manufacturer of poppers. Miller's press release, run
by most of the gay press, claimed that 'Jim' Curran
of CDC's AIDS branch had given him a guided tour
of the CDC and assured him there was no relationship
between poppers and AIDS. When Curran responded
with a letter saying that he had been misinterpreted, and
that poppers may playa role as cofactor in some of the
illnesses in the syndrome, his letter was ignored by the
gay papers who had run the press release from Miller.
Great Lakes Products followed through with a series
of ads in the Advocate, entitled 'Blueprint For Health',
which gave the impression that poppers, like vitamins,
fresh air, exercise and sunshine, were an ingredient in
the healthy lifestyle.
In 1987 a San Diego gay paper began running full-
page ads for poppers. The Windy City Times in Chicago
ran full-page ads, as well as articles attacking the critics
of poppers. Heartland, a mid-west gay paper owned by
Great Lakes Products, ran ads and articles defending
their product. The San Francisco Sentinel ran an ad that
warned of an impending ban on poppers ban, and urged
its readers to 'STOCK UP!' In 1992, three years after
poppers had been outlawed by act of Congress, a stand
at a gay street fair in Chicago offered iced tea for $1
and poppers for $5. In 1992 the manufacturer of RUSH
sent out a mail order ad to 'preferred customers'.
Hank Wilson concluded his presentation by mak-
ing the point: Poppers are easy and cheap to make,
they are highly profitable, and there is a demand for
them. Therefore, they will always be available. For
this reason, education is essential.
Do nitrites suppress the immune system?
The second afternoon session on 23 May dealt with in
vivo toxicological studies, two involving mice and one
involving human subjects.
First was Daniel Lewis of the National Institute
for Occupational Safety and Health. He was one of
those who conducted the 1982-93 CDC study on mice
that was the basis for the MMWR news item which
claimed to find 'no evidence of immunotoxic reac-
tions' (Centers for Disease Control, 1983). In that study
the doses were extremely low, approximating levels to
be encountered as background exposure (when used
as a 'room odorizer') rather than the intense dosages
328
encountered when using poppers as a drug (inhaling
directly from the bottle).
Lewis explained that, in determining the dose, they
had to adjust it below the level where they were 'losing'
the mice - however, the supplier of the mice later
disclosed that the mice had been suffering from a low-
grade infection. This means that their deaths may well
have been due to immunotoxicity - exactly what the
study conclusions claimed not to find. The end result
was that the dose was far too low to be meaningful.
The study was not blinded, as the mice inhaling IBN
vapors developed a 'yellowish tinge'. Although there
were no significant changes in body weight, there were
reduced liver and thymus weights, and an increase in
spleen weights. 100% of the exposed mice developed
methemoglobinemia. The white cell count went down
sharply.
The second study on mice was presented by Lee
Soderberg of the University of Arkansas. His mice
inhaled 900 ppm nitrite fumes for 45 minutes daily
for 14 days, then were allowed to rest for 1-3 days.
Then tests were performed. They found that there were
decreases in both body and spleen weight, the cells in
the spleen and in the blood were reduced, the response
to conA was reduced (-28%), the T-dependent cells
were very sharply reduced, accessory cell function was
affected (there was reduced ability to support prolifera-
tion of normal T-cells), and the macrophage functions
were greatly reduced (especially tumoricidal activi-
ty). The recovery of immune functions generally took
about a week; however, it took longer for macrophage
cytotoxicity to recover (about 2 weeks).
Soderberg and his colleagues concluded that
nitrites 'should be considered a hazardous substance',
since exposure of mice to nitrites via inhalation
impaired.
- T-dependent antibody responses
- T-mediated cytotoxity
- macrophage tumoricidal activity
In the question period Peter Duesberg raised the
issue of reversibility: What about something that goes
on for years? Analogies here would be the length
of exposure required to achieve a causal relationship
between cigarettes and lung cancer, or between alcohol
and cirrhosis. Soderberg replied that his team had 'no
data on more chronic exposure' .
The third speaker was William Adler of the Nation-
al Institutes of Health. His study was of eight human
volunteers, HIV-antibody-negative males, who inhaled
poppers three times per day for one week and them
intermittently for another week and a half. Baseline
immunological test batteries were run before, during,
and after exposure. The investigators found that the
main change was in natural killer (NK) cell activity,
which dropped very sharply. They concluded: 'The
results showed that exposure to amyl nitrite can induce
changes in immune function even after short exposure
to moderate doses'.
Do nitrites act as a cofactor in Kaposi's sarcoma?
The second day of the meeting, 24 May 1994,
addressed the key question: Do poppers play a role
in causing KS? The first speaker was Harry Haverkos,
who began by showing a slide indicating that there
appear to be four kinds of KS:
1. Classic KS, occurring among older men, indolent.
2. African KS: 25-40 age group, first indolent then
fatal in 5- 8 years.
3. Iatrogenic KS (e.g. renal transplant): indolent or
fulminant.
4. Epidemic or AIDS KS: gay white males, fulminant,
survival 1-3 years.
And he posed the question: 'Are these all the
same?'
Haverkos cited the cases of HIV-negative cases of
gay men with KS (16 in the practice of one physician
alone). He reviewed the epidemiological data, which
were inconsistent: four studies found a strong dose-
related relationship between the use of nitrites and the
development of KS, but other studies did not.
He cited a recent study which found that the volatile
nitrites are even more powerfully mutagenic than had
previously been thought. Iso-butyl nitrite vapors were
11 times as mutagenic as iso-butylin solution (Mirvish
et at., 1993).
Haverkos argued that the nitrite inhalants should
be considered a cofactor in the pathogenesis of KS
in AIDS, not only for epidemiological reasons, but
also because the distribution of KS lesions correlates
with areas of nitrite vapor exposure (nose, face, chest)
in many cases, and because plausible mechanisms of
action have been proposed (the formation of choles-
terol nitrite, a known carcinogen, and immune sup-
pression).
He argued that AIDS- related KS is unlikely to be
caused by an infectious agent, because very little KS
has been reported outside the gay male population;
because among gay men, KS is associated with the
white race and high socioeconomic status; because KS

in women with AIDS is no more likely among sexual
partners of bisexual men than among sexual partners
of heterosexual drug abusers; and because no one can
find the infectious agent.
Haverkos concluded with a call for further research,
with a particular emphasis on animal studies.
Other speakers in this section were Harold Jaffe
of the CDC, who was open to the possibility of a
direct role for poppers, and Haroutune Armenian of the
Johns Hopkins School of Hygiene and Public Health.
Although both men discussed survey research, neither
of them has professional experience in the field. The
high point of absurdity was reached when Armenian
claimed to find a strong, statistically significant neg-
ative correlation between poppers and KS! In other
words, the more poppers you use, the less likely you
are to develop KS. Obviously this violates common
sense and contradicts all other studies.
Robert Gallo revises the paradigm
The final speaker was Robert Gallo of the National
Cancer Institute. He began by saying that he wanted
to open up basic questions, and had no fixed opinion
regarding co-factors for KS - whether chemical, viral,
or a combination.
To my knowledge, this was the first time for Gallo
or any other top 'AIDS expert' to admit publicly that
HIV was not the primary cause of KS. He said: 'We
believe that HIV in KS is an enormous catalytic factor,
but there must be something else involved' .
After saying he did not believe that all Kaposi's is
one and the same disease, he went on to revise the most
basic premise of the AIDS paradigm: the assumption
that an underlying condition of 'immune deficiency' is
responsible for causing, indirectly, the various AIDS-
indicator diseases. He said:
There's a common belief that it's immune sup-
pression that is involved. Our data would argue
the opposite - that it's immune stimulation. You
can have Kaposi's in the absence of immune sup-
pression. I don't think there's any evidence that in
the older classic Kaposi's sarcoma - among older
men - that there's immune suppression. There's
not good evidence that there's immune suppres-
sion in the African form. And when you speak of
the immune suppression of the iatrogenic Kaposi's,
you have to keep in mind that there's also immune
stimulation.
And he posed a few additional questions:
329
Ask yourselves, who here has evidence that
Kaposi's is a true malignancy? Is it only polyclonal
hyperplasia that can harm and even kill? Or does
it really evolve into a true cancer? And if so, how
often? There's an enormous increase of Kaposi's
in HIV-infected gay men. What's the role of HIV?
Gallo then discussed findings from his laboratory.
A tumor cell has been isolated from KS, and inflam-
matory cytokines (ILl [interleukin 1], TNF [tumor
necrosis factor], and gamma interferon) are 'the very
likely initiatory events in creating this cell' . However,
unfortunately for the HIV-KS hypothesis, the inflam-
matory cytokines are also increased in gay men who
are HIV-negative. Nitric oxide, a by-product of nitrite
inhalation, is one possibility.
Some of those present were startled when Gallo
made the following statements:
I believe that HIV obviously plays a role in this dis-
ease. I think the epidemiology is not debatable. But
I think that there is more going on. I don't know
what that 'more going on' is. For me it's whatev-
er is accounting for the increase in inflammatory
cytokines.
I don't know if I made this point clear, but I think
that everybody here knows - we never found HIV
DNA in the tumor cells ofKS. So this is not directly
transforming. And in fact we've never found HIV
DNA in T-cells, although we've only looked at a
few. So in other words we've never seen the role of
HIV as a transforming virus in any way. The role
of HIV has to be indirect.
During the question period Peter Duesberg raised
the point that HIV couldn't always playa role in KS.
Gallo replied that the causes of classical or African KS
were unknown, and that an increase in the inflamma-
tory cytokines appeared to be implicated in AIDS-KS,
though he didn't know what caused the increase.
In response to a question about AIDS-related
dementia he replied: 'The mechanism of dementia in
HIV-infected people is totally unknown'.
Glen Hopkins, an activist from Los Angeles, raised
the question of high-dose, long-term exposure. Pop-
pers, after all, do promote mutagenesis. To this Gallo
replied: 'That's the most important thing, mutagenesis.
Also perhaps nitric oxide' .
Conclusions
In the final discussion, Gallo spoke strongly in favor
of an animal model, and said that Duesberg's research
ought to be funded.
330
The meeting closed with a consensus that con-
nections between nitrites and AIDS go beyond their
psychoactive consequences (promoting HIV transmis-
sion), and that understanding nitrite toxicity should
be a priority of the AIDS research agenda. These are
worthy sentiments, but meaningless if they are not put
into practice. NIDA has thus far failed even to give
serious consideration to the experiments proposed by
Duesberg, to study the effects of long-term exposure
of mice to nitrite fumes.
References
Centers for Disease Control, 1983. An evaluation of the immuno-
toxic potential of isobutyl nitrite. MMWR 64: 457-458.
Haley, T.H., 1980. Review of the physiological effects of amyl butyl,
and isobutyl nitrites. Clinical Toxicology 317- 329.
Haverkos, H.W., et ai, 1985. Disease manifestation among homosex-
ual men with acquired immunodeficiency syndrome: A possible
role of nitrites in Kaposi's sarcoma. Sexually Transmitted Dis-
eases October-December, 1985.
Haverkos, H.W. & J.A., Dougherty, (editors), 1988. Health Hazards
of Nitrite Inhalants. NIDA Research Monograph 83. National
Institute on Drug Abuse. Rockville, MD, 1988.
Lauritsen, J. & H. Wilson, 1986. Death Rush: Poppers & AIDS.
Pagan Press, NY 1986.
Lauritsen, J.P', 1987. Saying no to HIV: an interview with Prof. Peter
Duesberg, who says, 'I would not worry about being antibody
positive'. New York Native Issue 220, 6 July 1987.
Lauritsen, J.P', 1993. The AIDS War. Asklepios, N.Y.
Mayer, K. & 1. D'Eramo, 1984. Poppers: a storm warning. Christo-
pher Street Issue 78.
Mirvish, S.S., et ai., 1993. Mutagenicity of iso-butyl nitrite vaporin
Ames test and some relevant chemical properties, including the
reaction of iso-butyl nitrite with phosphate. Environmental and
Molecular Mutagenesis 21: 247-252.
Newell, G.R., M.R. Spitz & M.B. Wilson, 1988. Nitrite inhalants:
historical perspective. In NIDA Research Monograph 83
(Haverkos & Dougherty, 1988).
Quinto, I., 1980. The mutagenicity of alkylnitrites in the Salmonella
test (tr. from Italian). Bolletino Societa Italiana Biologia Speri-
mentale 56: 816-820.
Wood, R.W., 1988. The acute toxicity of nitrite inhalants. In NIDA
Research Monograph 83 (Haverkos & Dougherty, 1988).
 P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 331-336, 1996.
© 1996 Kluwer Academic Publishers.
The thinking problem in HIV-science
Phillip E. Johnson
UC Berkeley, Berkeley, CA, USA
Other contributors to this collection will be discussing
the scientific evidence regarding HIV and AIDS in
detail. To avoid duplicating their efforts, and to make a
contribution appropriate for a Professor of Law, I will
concentrate on the quality of the reasoning employed
in AIDS research. I have a healthy respect for scientific
methodology in its proper sphere. If I were persuaded
that the scientific method had been properly employed
to determine what AIDS is, how it is caused, and how
many people are at risk for AIDS, I would happily
accept the judgement of the scientific profession on
such matters. Unfortunately, however, the scientific
method has never been properly directed to determin-
ing the cause of AIDS or the extent of the claimed
epidemic. Instead of real science we have had only
HIV-science, which is something very different.
My starting point is a study of jury behavior, report-
ed for the public in a New York Times article by
Daniel Goleman. To the surprise of no one with
trial experience, it seems that many jurors employ
what the researchers described as 'faulty reasoning'.
Specifically:
These jurors decide on a version of events based
on a preliminary story they find convincing, often
at the time of the opening arguments, which then
colors their interpretation of the evidence so much
that they seize on whatever fits their verdict and
discount the rest. Such jurors tend to make up their
minds far earlier than others, and by the time they
enter the jury room for deliberation they cannot be
budged.
The nearly one-third of jurors whose decision-
making was most flawed, the study found, also
tended to be the most vehement about their cer-
tainty, and tended to argue for the most extreme
verdicts during the jury's deliberation. This gave
331
them undue influence in the final outcome. [N.Y.
Times, Nov. 29, 1994, p. C1.]
The Times story was not so much about jury behav-
ior as it was about human behavior, behavior which is
just as common in university faculty meetings as it is in
the jury room. Some people jump to conclusions early,
and are headstrong thereafter. They sometimes have
excessive influence over others because most people
are followers, and tend to go along in order to get
along. Headstrong, domineering personality types are
particularly likely to be found in highly competitive
situations, such as the worlds of big business and big
science. For example, a laboratory head has to be first
to publish a new theory or finding to get proper credit
and funding, and he has to have enough confidence in
his judgment to pursue a promising idea despite the
usual experimental disappointments and discouraging
evaluations by journal referees. When a scientist races
to put a speculative idea into practice he may turn out to
be ahead of his more cautious colleagues, and then we
will say he has positive qualities like insight, vision,
and courage.
When the same qualities are carried too far they
become pathological, and we describe the individual
as dogmatic or even willfully blind to nonconforming
facts. To keep dogmatism from getting out of hand we
rely on the tradition of criticism within the scientific
community, and especially the all-important require-
ment that scientific claims be based upon repeatable
experiments. The scientific method itself is trustwor-
thy, when it can be properly applied. It is in the method,
however, and not the fallible human nature of the sci-
entists, that we should place our trust.
The importance of criticism was vividly illustrated
by the notorious 'cold fusion' episode. The 'discov-
erers' seem to have been carried away by the magni-
tude of what they thought they had discovered, and
they were persuasive enough to induce eager univer-
sity officials to commit university resources recklessly
332
to their cause. What kept things from going too far was
that the scientific community did not meekly accept
claims made at a press conference, but insisted upon
seeing experimental results that others could replicate.
When such criticism and independent reexamination
does not occur, however, scientists are not necessarily
more trustworthy than other people. Like the domi-
neering jurors in the study, they may quickly adopt a
theory they find appealing, and refuse to reconsider it
when the disconfirming facts start to pile up.
HIV-science began just as cold fusion, with a dis-
covery announced at a press conference by scientists
and public officials eager for glory and funding. The
difference was that there was no follow-up investiga-
tion to discern whether the discovery of 'the virus that
caused AIDS' was genuine. In retrospect, it is clear that
no proof that HIV is the cause of AIDS was presented
either at Dr. Robert Gallo's April, 1984, press confer-
ence, or in the four papers his team published a month
later in Science. All Gallo claimed was that many, but
not all, AIDS patients tested positive for antibodies to
the retrovirus Gallo was then calling H1LV-III.
Warning signs that Gallo's virus might not be the
cause of AIDS were abundant. Why wasn't the virus
itself found in quantity in all of the AIDS patients? How
abundant and active was the virus? Mightn't the pres-
ence of antibodies imply that the patients had devel-
oped immunity to the virus, rather than that the virus
was destroying their immune systems? Above all, by
what observable mechanism was this retrovirus not
only destroying the immune system, but also causing
such disparate conditions as Kaposi's sarcoma (here-
after KS) and dementia? The mystery was all the deeper
because the virus was supposed to perfQrm its destruc-
tive work many years after infection and after being
reduced to near non-existence by the very antibodies
that provided the evidence of infection.
In a normal scientific atmosphere, all these issues
would have been debated for months (at least) in sci-
entific conferences and journals before the profession
would seriously consider settling upon HIV as the
cause of AIDS. Gallo's logic amounted to this: 'we
have found antibodies to a previously unknown retro-
virus in many of our AIDS patients; therefore this
retrovirus causes all the cases of that vaguely defined
syndrome we have labelled AIDS'. Why didn't the
other scientists notice that this reasoning was prepos-
terous?
There can be no excuses for such a massive profes-
sional fiasco, but there are circumstances that make it
partly understandable. Scientists customarily assume
that papers published in leading journals like Science
have been subjected to thorough, critical peer review.
In fact the papers had obviously been rushed into pub-
lication. The haste was partly due to the perceived
extent of the public health emergency, and partly due
to the need to snatch credit for the discovery from the
French, who had first isolated the virus and trustingly
sent a sample to Dr. Gallo. Once the discovery was
announced, the race was on to find a cure or vaccine,
with grant money and glory in prospect.
No grants were offered for efforts to disprove the
official theory. If anyone had stopped to investigate
whether the virus really was guilty as charged, he
would have looked like a fool for wasting valuable
time that could be better spent looking for a cure. If
such a researcher actually did find reason to doubt the
official theory , he could look forward not to glory
but to facing the wrath of disappointed colleagues. For
cold fusion there was an opposition party of skeptical
physicists in place, eager to debunk the pretensions
of the chemists who claimed to have made the dis-
covery. AIDS research was a one-party state from the
beginning.
The HIV theory was immediately triumphant
because it was the kind of solution to the AIDS mystery
that all the major players wanted to see. Virologists like
Dr. Gallo, who had been unsuccessful in the search for
cancer-causing viruses, had found years of guaranteed
funding for their very expensive laboratories. Epidemi-
ologists at the Centers for Disease Control gained new
importance and prestige. Political officials in the Regan
administration, pummelled for their alleged inaction in
the face of the 'pandemic', could point to a smashing
success and predict speedy development of a vaccine.
Organizations of AIDS patients had cause to hope for a
cure, and they were assured also that, since 'everyone
is at risk' for what would eventually be called 'HIV
disease' , an unpredictable new virus and not their own
conduct was to blame for their condition. Drug compa-
nies - especially the influential Burroughs Wellcome,
manufacturer of AZT - stood to make a fortune. No
one had a motive to doubt, and so no one doubted.
No one, that is, until Peter Duesberg surfaced with
his famous paper in Cancer Research in 1987. By
then it was too late for reconsideration. The research
community was totally committed to HIV and its pres-
tige was at stake. Moreover, thousand of patients were
being treated with AZT, a highly toxic drug whose
presumed efficacy depended entirely on the premise
that it was killing HIV-infected cells. If the HIV the-
ory was wrong, these people were being poisoned.

Those responsible for approving and prescribing the
drug were not eager to consider whether they might be
gUilty for such irresponsibility.
Even so, one might have expected the scientific
community to take such a challenge seriously. Dues-
berg was one of the world's most prestigious virolo-
gists, and his logic was impressive. He pointed out that
retroviruses by their very nature do not kill the cells
they infect, and would become extinct if they did. That
they must cooperate with the cells in order to repro-
duce explained why they were suspected as possible
cancer causes - cancer being a matter of the patho-
logical growth and multiplication of cells rather than
their disappearance. How could the research commu-
nity be certain that HIV was the cause of AIDS if no
mechanism of cell-killing could be found, and if cell-
destruction seemed inconsistent with what was known
about the nature of the virus?
Duesberg argued without significant contradiction
that Koch's postulates, the accepted standard for deter-
mining a microbial cause, had clearly not been satis-
fied. HIV was not found in all persons with AIDS-
defining conditions; on the contrary, active virus was
very difficult to find even in persons dying of AIDS.
The presence of antibodies is not evidence that a per-
son is currently being damaged by a virus; rather it
is evidence that the immune system has successfully
countered the infection. HIV had not been shown to
cause AIDS when injected in healthy subjects (exper-
imental chimpanzees infected with HIV). The proba-
bility therefore was that HIV was just one of many
'passenger' viruses that could be found in the bodies
of many AIDS patients. Where was the proof that it
was the cause?
The research community simply ignored these
trenchant criticisms for over two years. When the
HIV establishment finally did respond to Duesberg in
Nature in 1989, the paper by Robin Weiss and Harold
Jaffe took HIV causation for granted, defended the
official position with a series of question-begging argu-
ments, and based its main line of argument on outright
ridicule. I was shocked.
The same method of argument has continued to
the present day. Serious questions are evaded with
frivolous answers. Serious question: Does it cast doubt
on the HIV theory that HIV fails to cause AIDS in
infected chimps? Frivolous answer: That shows only
that HIV causes AIDS in humans but not in chimps.
Besides, a different virus ('SIV') causes a different
syndrome in monkeys. Serious question: How can
HIV deplete the cells of the immune system when
333
it infects only a small fraction of them? Frivolous
answer: Genetic sequences associated with HIV (not
active virus) can be found in relative abundance in
the lymph nodes by use of the peR technique. Seri-
ous question: Why are there so many acknowledged
cases of AIDS-defining conditions like KS and low T-
cell counts in the absence of HIV infection? Frivolous
answer: When HIV is present it is the cause of those
conditions; when it is absent, they are caused by some-
thing else.
I could go on with examples, but the reasoning is the
same in every instance. Serious questions are met with
frivolous answers, because HIV science is practiced
by people like those domineering jurors, who made up
their minds before all the facts were in and then stopped
listening. The HIV theory has become axiomatic, and
so even patently question-begging answers will suffice
to explain away disconfirming evidence. The HIV sci-
entific establishment gets away with this unprofession-
al behavior because AIDS research is tightly controlled
from the top, and because acquiescent science reporters
and editors have allowed themselves to be bamboozled
by self-serving propaganda. The HIV scientists claim
that it is somehow 'homophobic' to question the HIV
theory, or that reporters who publicize the mounting
reasons for doubt will be responsible for furthering the
spread of the epidemic. Few voices in the biomedical
research community, which depends on HIV money
for its funding, are raised in protest. The example of
Peter Duesberg, who lost virtually all his funding as a
consequence of his dissent, stands as a warning to all
the others.
I have been associated with Duesberg in the
HIV/AIDS controversy for about five years, as a law
professor with a particular interest in scientific reason-
ing. I first met Duesberg because he came to ask my
advice after he was refused renewal of his NIH Out-
standing Investigator Grant. From the context, it was
apparent that a man who had formerly been a prince of
science was on a blacklist. Duesberg wanted to know
if there was some legal remedy, considering that the
panels that had reviewed his funding were composed
largely of persons with personal and financial interests
in the theory he was questioning. I had to tell him
that the courts would defer to the collective judgment
of the research community, and that he would need
to develop considerable support among scientists to
have a chance of prevailing in any legal or administra-
tive proceeding. In the course of these conversations,
I gradually became more and more familiar with the
disputed scientific issues.
334
For some time I saw the controversy mainly as a
free speech question: a prominent scientist had voiced
apparently rational dissent to orthodox opinion, and
instead of being taken seriously, he was being pun-
ished. I thought he deserved a fair hearing, but was
unsure about what the outcome of such a hearing ought
to be. Duesberg and other dissenters (like Harvey Bialy
and Robert Root- Bernstein) clearly had some good
arguments against the HIV theory, but they didn't seem
to have a viable alternative. Duesberg's alternative the-
ory - that drug use was responsible for a good part of
the AIDS epidemic - seemed to have its own problems.
I was particularly concerned by the apparent absence
of documented cases of 'full blown AIDS' with no
HIV infection, although there were rumors that such
cases existed.
Two experiences in 1992 convinced me that Dues-
berg was right, at least in the negative part of his case,
and that an unbiased reexamination of the whole AIDS
phenomenon was overdue. The first was the emergence
of the 'AIDS without HIV' cases at the international
conference in Amsterdam in the summer of 1992, and
especially the dishonest handling of these cases by the
CDC and NIH. Given that the HIV scientists them-
selves were by then admitting that the mechanism of
HIV causation was a complete mystery, any flaw in
the crucial correlation evidence relied upon to prove
causation was of great significance. Clearly the reve-
lation that persons apparently mortally ill with AIDS
sometimes had no HIV infection, even when the most
strenuous measures were employed to find the virus,
called for a thorough reconsideration of the theory.
The case for reconsideration was particularly strong
because the acknowledged cases of 'AIDS without
HIV' were probably only the tip of the iceberg. It was
difficult for such cases to be noticed due to the HIV-
biased definition of AIDS that was being employed.
AIDS is not a disease defined independently of HIV,
but a syndrome of up to 29 previously known diseases
which are diagnosed as AIDS if there is also either
the real or suspected presence of HIV antibodies. If all
antibody-negative cases of AIDS- defining conditions
were listed as 'AIDS without HIV' , the appearance of
a close correlation between HIV and AIDS would col-
lapse altogether. And yet the supposed correlation was
the only proof that HIV is the cause of AIDS.
Instead of facing the issues squarely and publicly,
the CDC representatives at the Amsterdam meeting,
who had previously known about some of the anoma-
lous cases but concealed their existence, buried the
real issue under a flood of bogus publicity concerning
a feared 'new virus' that might be causing the anoma-
lous cases. At this point I became convinced that we
were dealing with a scientific establishment that was
intent upon preserving a favored story regardless of
the facts - very much like those jurors described in the
New York Times report.
The second experience that brought me to a deci-
sion was that of participating in the pre- publication
review of Duesberg's major paper, 'AIDS Acquired
by Drug Consumption and Other Noncontagious Risk
Factors', which appeared in the international journal
Pharmacology and Therapeutics in 1992. Duesberg
had asked me to give a critical reading to an early
draft of the paper, and I was sufficiently interested to
go through it line by line and source by source. By
accident I had an unusual additional role, because the
supervising editor for Duesberg's paper was Professor
David Shugar of the University of Warsaw, who could
communicate efficiently with Berkeley only by email.
I was just then learning the ways of the internet, and
Duesberg hardly knew what email was.solbecame by
default the go-between for the author and editor. Many
criticisms came from mUltiple editorial consultants,
and all had to be considered. Through this process I
became intimately familiar with the jots and tittles of
the HIV/AIDS controversy, and I became convinced
that Duesberg was practicing honest science and the
HIV establishment was not.
What convinced me was not any single scientific
point but the accumulation of evidence from all direc-
tions, and particularly the monolithic refusal of the
HIV-scientists to take the evidentiary problems seri-
ously. Duesberg was engaged in the scientific process
of testing the HIV theory, while his opponents were
ignoring the facts or responding to particular points on
an ad hoc basis with no concern for overall consis-
tency. The African statistics, for example, would be
cited offhandedly to show that 'worldwide', men and
women are equally at risk for AIDS. (AIDS is almost
90% male in the United States and Europe). When-
ever the African statistics presented a problem for the
HIV theory, on the other hand, they would be just
as offhandedly dismissed because 'everybody knows'
that the African statistics are unreliable.
Even the admission that Kaposi's sarcoma is not
caused by HIV did not cause the HIV-scientists to
pause for reconsideration, or to reexamine the thou-
sands of cases that were diagnosed as 'AIDS' without
antibody testing, solely on the basis of KS. KS occurs
frequently in HIV-negative persons and in America is
specific to gays rather than other HIV-infected groups;

hence something specific to this group, like the use
of amyl nitrites (poppers), must be the primary cause
of KS. Virologists, who outrank toxicologists in the
hierarchy of HIV- science, prefer to attribute KS to
a mystery virus which has never been discovered. In
any case, the virus is not HIV. KS was the original
AIDS-defining disease, and the discovery of KS in
many HIV-free gay males should have sparked a major
reexamination of the assumptions upon which the HIV
theory was founded. It actually had no effect on HIV-
science whatever. Observing this consistent refusal to
reason scientifically convinced me that HIV-science is
pseudo-science, and that its inflated claims are unwor-
thy of belief.
This pattern of irrationality and misrepresentation
in HIV-science has continued to the present. First
example: official statistics show that the total num-
ber of HIV positive persons in the U.S. population has
not increased an iota since antibody testing began; it
has stayed at a flat one million. Nonetheless, this figure
is continually reported to the public as if it were the
result of a steady increase, and the same virus is report-
ed to be newly infecting millions of persons annually
in places like Africa, where reliable testing procedures
do not exist.
A New York Times story by the well-connected
Lawrence Altman reported on March 1, 1994, that
the CDC would soon amend the U.S. total from one
million to between 600 000 and 800 000, due to more
recent studies that supported a lower figure. As of mid-
1995 the downward change has not been announced,
and there has been no public discussion of this impor-
tant subject. Why not? A candid discussion of HIV
and Aids statistics would make clear that the extent
of the 'epidemic' had been exaggerated, and that the
incidence of HIV infection in the United States is not
increasing. Public understanding of the fact would
damage the credibility of HIV researchers who have
been hyping a growing epidemic, and would inevitably
generate skepticism about whether HIV infection is
truly skyrocketing as claimed in Africa and Asia.
For similar reasons, the HIV establishment con-
tinues to advertise that 'everyone is at risk', and that
'AIDS does not discriminate'. The experts know that
AIDS remains confined to the original risk groups and
is not spreading to drug-free heterosexuals, but to admit
this would be to admit both that HIV-science is over-
funded in comparison to far greater threats to health,
and that predictions based on the HIV theory have
consistently been falsified.
335
Second example: The HIV establishment has made
much of a 1994 paper by Dean Mulder et al, in Lancet
[vol. 343, p. 1021], titled 'Two-YearHIV-1-Associated
Mortality in a Ugandan Rural Population'. This study
of Uganda villagers showed that those who tested pos-
itive for antibodies had a much higher death rate than
those who did not, especially in the age group 25-34.
Officials from the CDC and other AIDS agencies cite
this study as proving that an AIDS epidemic caused by
HIV is ravaging Africa.
What the HIV propaganda does not say is that the
subjects did not die of AIDS. The cause of death was
reported for 64 antibody-positive subjects, and of this
group only 5 were diagnosed as AIDS under the very
broad 'Bangui' (African) definition, which requires
only conditions like sustained weight loss and persis-
tent diarrhoea. Moreover, it is erroneous to assume
that the Ugandans who tested positive were actually
HIV-infected, because false positives on antibody tests
are common, particularly in Africa. That this finding
of mostly non-AIDS deaths among persons who may
or may not have been HIV-infected was claimed to
support the HIV theory of AIDS and the existence of
an African HIV/AIDS pandemic is eloquent testimony
to the closed mindset and intellectual dishonesty that
rules HIV research.
In fairness, I cannot say that all evidence present-
ed in favor of the HIV research establishment is that
obviously illogical or that easily refuted. It is said that
over 100 OOO papers on HIVI AIDS have been pub-
lished, virtually all of them funded by sources totally
committed to the HIV theory. Some of those papers
claim a high correlation between AIDS- defining con-
ditions and HIV-positivity in certain populations, and
an absence of correlation with other suspected fac-
tors, such as drug use. Evaluation of specific studies
is a job for specialists with access to the raw data.
A general observer such as myself can only state the
obvious: first, correlation studies are only valid when
the researchers are scrupulously careful to control for
all possible alternatives; and second, a research estab-
lishment bent on supporting a theory and with billions
of dollars at its disposal will always be able to supply a
few confirming studies. HIV-science has demonstrated
again and again that it does not deserve the benefit of
the doubt.
In short, the problem with HIV-science is not that
any single piece of evidence conclusively falsifies the
theory that a pandemic caused by HIV is ravaging the
planet. It is that evidence is piling up in all directions
that cumulatively calls every aspect of the theory into
336

question. The HIV-scientists respond with the usual manipulation of statistics; and even outright misrep-
weapons of pseudoscience: unexamined assumptions; resentation. It is time for the scientific community to
ad hoc, question-begging arguments; reliance upon insist that HIV-science be abandoned, and that real
the least reliable evidence rather than the most reliable; science take its place.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 337-341, 1996.
© 1996 Kluwer Academic Publishers.
The incidence quagmire
John Lauritsen
26 St. Mark's Place, New York, NY 10003, USA
The incidence of AIDS has concerned me ever since
the spring of 1987, when I reviewed the Institute of
Medicine's book, Confronting AIDS (Lauritsen, 1987).
In that review I criticized the CDC's AIDS projec-
tions through 1991 as being grossly exaggerated and
based on little if any evidence. As the years passed
it became painfully obvious that the CDC's projec-
tions had indeed been far too high, even after they had
greatly expanded their surveillance definition of AIDS
in late 1987.
A year and a halflater I analyzed the CDC's surveil-
lance statistics for 12 September 1988, and concluded
that the incidence of AIDS in the United States was
peaking, even with the expanded definition. By this
time it was necessary to present the data using a seg-
mented bar chart, where the bottom segments for a
given time period represented cases qualifying under
the old definition and the top segments represented cas-
es qualifying only under the new definition (Lauritsen,
1988a). I commented that the CDC's projections from
1987 were becoming increasingly absurd.
In April 1990 I discussed a debate that had erupted
in the pages of the Journal of the American Medical
Association over AIDS incidence. Two experts in epi-
demiology, Dennis Bregman and Alexander Langmuir,
wrote an article, 'Farr's Law Applied to AIDS Projec-
tions', in which they demonstrated that the AIDS epi-
demic had already peaked in the United States. (Breg-
man & Langmuir, 1990). For this politically incorrect
viewpoint they were attacked by two separate editori-
als written by government scientists (Gail and Brook-
meyer, 1990; Morgan, Curran & Berkelman, 1990). I
defended the analysis of Bregman and Langmuir, and
made a segmented bar chart of AIDS incidence up to
27 February 1990 (Lauritsen, 1990a). In this chart a
broken line shows the CDC's projections soaring far
above the actual incidence (see graph).
When the CDC expanded the surveillance defini-
tion of AIDS still again, in January 1993, I gave up,
337
and repudiated my previous attempts to analyze AIDS
incidence. It was bad enough trying to compare apples
with oranges, but when kumquats and candy bars were
thrown into the equation, it was time to quit. Consider-
ing the utterly spurious nature of the AIDS-definition,
I was wrong ever to think in terms of incidence. I was
wrong to discuss Gaussian distributions. I was wrong
to make bar charts.
You cannot track a non-existent entity
From the very beginning I realized that something was
very wrong with the basic concept of 'AIDS', but it
is one thing to sense something, and quite another to
understand it analytically. Several AIDS-critics were
influential in clarifying my thinking on the core prob-
lem of AIDS: whether it actually exists in any rationally
definable way.
Harry Rubin, Professor of Molecular Biology at
Berkeley, the man who virtually created the science of
retrovirology, gave a talk in Washington, DC in 1988,
in which he expressed skepticism regarding the sim-
plistic notion that the 20 (at the time) AIDS-diseases
constituted a single entity caused by a single virus.
This he referred to as 'Cartesian reductionism' - the
tendency to reduce complex phenomena to a single
cause. Rubin's comments not only cast doubt upon the
HIV-AIDS hypothesis, but upon the very existence of
'AIDS' as well (Lauritsen, 1988b).
Peter Duesberg, also Professor of Molecular
Biology at Berkeley, has consistently ridiculed the
Centers for Disease Control (CDC) definitions of
'AIDS', expressed by the formula: Indicator Dis-
ease + HIV = AIDS. The first part of the equation is
absurd because of the extreme heterogeneity of the offi-
cial AIDS-indicator diseases or conditions (see below).
The second part of the equation is also absurd, because
the HIV requirement can be satisfied in so many dif-
ferent ways: a positive result on the highly inaccurate
HIV-antibody tests; a positive result on the Polymerase
338
Chain Reaction (PCR) test; actually cultivating the
virus from a patient's blood plasma (which is almost
never done - when attempts are made, it is impossi-
ble to cultivate HIV from the plasma of at least 50%
of 'AIDS patients'). Or, as is done in about half of
the 'AIDS' diagnoses, simply 'presuming' that HIV is
present. As Duesberg mischievously points out, deme-
tia + HIV = AIDS, but dementia - HIV = stupid.
Kawi Schneider in Berlin has vigorously polemi-
cized for years against the core mythology of 'AIDS'.
In a 1989 article he wrote: "AIDS' is a fraudulent
diagnostic label that, in conjunction with statistical
patchwork, has created an epidemiological castle in
the air, which can be considered the first freely invent-
ed pseudo- epidemic' (Schneider, 1989). In a recent
letter to me he commented:
Even from the orthodox stand point, 'AIDS' is not
the name of a disease, but rather the name of a coin-
cidence, interpreted as causation, oflab parameters
(antibodies and T-cell counts) and at least one item
from the list of 30 conventional diseases known as
'AIDS-indicator diseases' .... I never write or say
'person with AIDS', but 'person with an AIDS-
diagnosis', never 'spread of AIDS' but 'spread of
AIDS-diagnoses' ... never 'HIV-infection' but
'antibody presence indicated by a test' (29 March
1993).
For my part, I have coined the phrase, "AIDS' is
a phony construct', which has begun to catch on. For
several years I have made it my practice to put 'AIDS'
in quotation marks, to emphasize the dubiousness of
the basic concept. Some people find this annoying, and
I'm sure that it is, but constant reminders are necessary
to avoid slipping back into the mind-set ofthe orthodox
AIDS-paradigm. This is exactly what happened with
me on the question of incidence. One part of my mind
saw clearly that 'AIDS' was a phony construct. At the
same time, another part of my mind - misled, per-
haps, by my professional experience in tracking things
statistically, and my fondness for making charts and
graphs - blithe:y went about analyzing the incidence
of a non-existent entity.
To further appreciate the absurdity of the CDC's
surveillance definition of 'AIDS', let's look at the offi-
cial AIDS-indicator diseases, which now appear to
number twenty nine.
The 29 AIDS-indicator Diseases
Last January the CDC expanded the surveillance defi-
nition of 'AIDS' still another time. Since I wanted to
know exactly what and how many the indicator dis-
eases were, I called the CDC, where I spoke to Press
Officer Kent Taylor. My request turned out to be more
difficult than I had imagined it would be. The CDC had
never thought to compile a simple list of the indicator
diseases, let alone a numbered list. But Taylor was
resourceful, and got back to me in a couple of hours
with the raw material from which I myself have made
a numbered list.
The following list is taken from a table 'AIDS-
Indicator diseases diagnosed in patients reported in
1991, by age group - United States' (Centers for Dis-
ease Control, 1992a):
1. Bacterial infections, multiple or recurrent (applies
only to children)
2. Candidiasis of bronchis trachea or lungs
3. Candidiasis of esophagus (either a 'definitivediag-
nosis' or a 'presumptive diagnosis')
4. Coccidioidomycosis, disseminated or extrapul-
monary
5. Cryptococcosis, extrapulmonary
6. Cryptococcosis, chronic intestinal
7. Cytomegalovirus disease other than retinitis
8. Cytomegalovirus retinitis (either a 'definitive diag-
nosis' or a 'presumptive diagnosis')
9. HIV encephalopathy (dementia)
10. Herpes simplex, with esophagitis, pneumonia, or
chronic mucocutaneous ulcers
11. Histoplasmosis, disseminated or extrapulmonary
12. Isosporiasis, chronic intestinal
13. Kaposi's sarcoma (either a 'definitive diagnosis' or
a 'presumptive diagnosis')
14. Lymphoid interstital pneumonia and/or pulmonary
lymphoid hyperplasia (either a 'definitive dia~no­
sis' or a 'presumptive diagnosis')
15. Lymphoma, Burkitt's (or equivalent term)
16. Lymphoma, immunoblastic (or equivalent term)
17. Lymphoma, primary in brain
18. Mycobacterium avium or M. kansas ii, disseminat-
ed or extrapulmonary (either a 'definitive diagno-
sis' or a 'presumptive diagnosis')
19. M. tuberculosis, disseminated or extrapulmonary
(either a 'definitive diagnosis' or a 'presumptive
diagnosis' )
20. Mycobacterial diseases, other, disseminated or
extrapulmonary (either a 'definitive diagnosis' or a
'presumptive diagnosis')
21. Pneumocystis carinii pneumonia (either a 'defini-
tive diagnosis' or a 'presumptive diagnosis')
22. Progressive multifocalleukoencephalopathy
23. Salmonella septicemia, recurrent

24. Toxoplasmosis of brain (either a 'definitive diag-
nosis' or a 'presumptive diagnosis')
25. mv wasting syndrome
On 8 December 1992, a letter was mailed by the
CDC to State Health Officers, informing them: 'On
January 1, 1993, an expanded surveillance definition
for AIDS will be effective' (Centers for Disease Con-
trol, 1992b). The following AIDS-indicator conditions
were added to the list:
26. A CD4+ T-lymphocyte count <200 cells/ JLL (or a
CD4+ percent <14)
27. Pulmonary tuberculosis
28. Recurrent pneumonia (within a 12-month period)
29. Invasive cervical cancer
To my knowledge, I an the first writer to compile a
numbered list of the official AIDS-indicator diseases or
conditions. It is a very mixed bag. Many of the diseases
are caused by funguses: for example, candidiasis, coc-
cidioidomycosis, cryptococcosis, histoplasmosis, and
Pneumocystis carinii. Others are caused by bacteria,
like salmonella. Others, by mycobacteria, like tuber-
culosis. Still others, by viruses, like cytomegalovirus
or herpes. And still others, like the various cancers and
neoplasms, including lymphoma and Kaposi's sarco-
ma, have no established etiology. And still others, like
dementia or wasting, are poorly defined and can have
many different causes.
Dementia is presented on the list as 'mv
encephalopathy', but it is difficult to imagine how
a retrovirus, like mv, could cause encephalopathy.
Retroviruses, by their very nature, can only infect cells
that are capable of undergoing cell division. Brain cells
do not divide. Therefore, mv does not and cannot
infect brain cells.
Some of the indicator diseases/conditions can be
diagnosed presumptively. This is a charming situation.
Not only can my be diagnosed presumptively, but
some of the indicator diseases as well. This means that
a physician, following the CDC's rules, would be able
to diagnose someone who behaved eccentrically, or
had difficulty swallowing, or had a bad cough, or just
seemed in poor health, as having 'AIDS' on the basis
of a presumptive diagnosis of mv infection coupled
with a presumptive diagnosis of toxoplasmosis of the
brain, or candidiasis of esophagus, or Pneumocystis
carinii, or a mycobacterial infection, or whatever.
One also notices that two items on the list are
known and expected consequences of AZT therapy:
lymphoma and wasting. I'll have more to say about
this below;
339
'AIDS' cases - present andfuture
In February 1993 the CDC issued an 'mY/AIDS
Surveillance Report' which covered all cases reported
through December 1992 (Centers for Disease Control,
1993). As of that date, a total of 253,448 Americans
had received a diagnosis of 'AIDS' , of which 249,199
were adult or adolescent cases and 4249 were pediatric
(under 13 years) cases.
Although people were undeniably sick, the diag-
noses themselves were arbitrary and irrational. They
were based on the false premise that mv is pathogenic.
They were based on changing and inconsistent surveil-
lance criteria. It would be wrong even to think of track-
ing incidence for such diagnoses, and I shall not do so.
Never again will I make a bar chart of 'AIDS' inci-
dence!
According to the report, 171,890 Americans had
died of 'AIDS' as of 31 December 1992; 169,623 were
adults or adolescents and 2,267 were children under 13.
The truth of the matter is that most of these people died
of medical incompetence. They died because they were
never warned against the things that made them sick
in the first place. They died because they were given
toxic drugs that they didn't need.
Though it would be erroneous to speak of 'AIDS-
incidence', it is still reasonable to wonder how many
people in the future will become sick in ways that
will be diagnosed as 'AIDS'. Five years ago I was
optimistic: it looked as though 'AIDS-incidence' had
peaked. Now I am much more pessimistic. On the
horizon I see a large crop of new' AIDS' cases resulting
from two phenomena: 1) a resurgence of drug use
among gay men, and 2) the mass administration of
AZT to healthy individuals who are mY-positive.
Gay drug abuse
In the last couple of years, gay men in San Francis-
co and New York City, two epicenters of the 'AIDS
epidemic', have gone back to the levels of drug abuse
and promiscuity obtained in the 70s and early 80s. For
the most part, they are young men who are new to
the gay scene. (Many and perhaps even most of those
who behaved this way in the 70s have already died of
'AIDS').
On Fire Island in August 1992, several thousand
gay men attended a 'Morning Party', which was held to
benefit Gay Men's Health Crisis (GMHC). One person
who was there told me that at least 95% of them were in
a state of extreme intoxication from alcohol and such
340
drugs as Ecstasy, poppers and cocaine. The playwright
Larry Kramer made the following comments:
I loathed the Morning Party. The Morning Party
sent me into a depression I cannot begin to describe.
After 12 years of the plague, I should come back
and see the organization that was started in my
living room having a party like that! First of all, to
call it a morning party - the irony of the play on
the word mourning.
There were 4000 or 5000 gorgeous young kids
on the beach who were drugged out of their minds
at high noon, rushing in and out of the Portosans
to fuck, all in the name of GMHC (Zonana, 1992).
It is now late March 1993, and I have just returned
from a trip to London, where there is an explosion
of drug use in the gay scene. Every Saturday night an
estimated 2000 gay men attend a dance club where drug
consumption is the main acti vity. According to London
sources, virtually 100% of the men are on drugs, from
3:00 in the morning, when the club opens, until it
closes many hours later. Especially popular is a variety
of Ecstasy, whose ingredients are claimed to include
heroin. The police do nothing, and everyone believes
that they are paid off. Poppers (nitrite inhalants) are
sold legally in London. No one seems to think they
even count as drugs, as gay physicians, writing in the
gay press, have said that poppers are harmless.
None of the major AIDS organizations have prop-
erly warned about the dangers of drugs. At most, their
risk-reduction literature has urged people to use alcohol
and drugs in moderation, so as not to affect the 'judg-
ment'. Drugs are portrayed as risky only to the extent
that they might facilitate a lapse into 'unsafe sex'. Pop-
pers - which cause genes to mutate, which cause severe
anemia, which form carcinogenic compounds, which
kill through cardiovascular collapse or stroke, which
suppress the immune system - are depicted as bad only
if they cause someone to forget about condoms.
AZT-AIDS
The DNA-terminator drug, AZT, is capable of causing
'AIDS' according to official CDC criteria. Among the
known toxicities of AZT are lymphoma and cachexia,
or wasting, which are on the list of AIDS-indicator dis-
eases (Lauritsen, 1990b, 1993). In addition, a patient
debilitated by the most toxic drug ever prescribed for
long-term use will become vulnerable to many oth-
er diseases, some of which are also on the list. The
salient point here is that a large though unknown num-
ber of healthy, HIV- positive individuals- at minimum,
many tens of thousands - are currently on AZT thera-
py. Within a few years, nearly all of them will be dead.
Most of the deaths will be attributed to 'AIDS' .
If the mainstream AIDS organizations were gen-
uinely concerned about 'fighting AIDS' (one of their
favorite slogans), they would warn the public about
the dangers of the nucleoside analog drugs (AZT, ddl,
ddC, d4 T, etc.). They have done just the opposite. Such
organizations as GMHC in New York City and Ter-
rence Higgins Trust (THT) in London have colluded
with AZT's manufacturer, Wellcome, to promote the
deadly nostrum (Lauritsen, 1993). I see no reason to
pull punches here: GMHC and THT have played an
active and important role in causing drug-induced ill-
nesses that are diagnosed as 'AIDS'.
An epidemic of lies
A core fallacy inherent in any discussion of AIDS-
incidence is this: not only the diagnoses, but to a large
extent the AIDS- indicator diseases as well, are the
consequences of disinformation. By this I mean not
only disinformation leading to iatrogenic AIDS (the
promotion of harmful drugs like AZT), but also risk-
reduction disinformation. Intravenous drug users have
been told, through Public Health Service propaganda,
that injecting heroin and other drugs is safe, so long
as the needle is clean. Gay men have been told that
poppers and other drugs of the gay subculture are safe,
so long as 'safe sex' is practised.
The 'epidemic' would subside quickly if the truth
were told.
References
Bregman, D.G. & A.D. Langmuir, 1990. FaIT's Law applied to AIDS
projections. JAMA 263: II.
Centers for Disease Control, 1992a. AIDS-indicator diseases diag-
nosed in patients reported in 1991, by age group. HIV/AIDS
surveillance report. January, 1992.
Centers for Disease Control, I 992b. On January I, 1993, an expand-
ed surveillance definition for AIDS will be effective (letter sent
to State Health Officers, 8 December, 1992).
Centers for Disease Control, 1993. HIV I AIDS Surveillance Report.
February, 1992.
Gail, M. & R. Brookmeyer, 1990. Projecting the incidence of AIDS.
JAMA263.
Lauritsen, J.P., 1987. Review of Confronting AIDS, Institute of
Medicine. New York Native. Issue 203, 9 March, 1987.
Lauritsen, J.P', 1988a. AIDS incidence dropping. New York Native.
Issue 286, 10 October 1988.
Lauritsen, J.P., 1988b. Kangaroo Court Etiology. New York Native.
Issue 264, 9 May 1988.
Lauritsen, J. P., 1990a. Debate over AIDS incidence. New York
Native. Issue 363, 2 April 1990.

Lauritsen, J.P., 1990b. Poison By Prescription: The AZT Story.
Asklepios, NY.
Lauritsen, J.P., 1993. The AIDS War. Asklepios, NY.
Morgan, M., J. Curran, & R. Berkelman, 1990. The future course of
AIDS in the United States. JAMA 263: 11.
341
Schneider, K.W., 1989. 'AIDS' - die neue Religion. Raum & Zeit.
June/July, 1989.
Zlmana, V., 1992. Kramer vs. the world (interview with Larry
Kramer). The Advocate. No 611, 1 December, 1992.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 343-346, 1996.
© 1996 Kluwer Academic Publishers.
ThemVtest
Celia Farber
216 W. 102nd St. #7B, New York, NY 10025, USA
Whether or not people ought to submit to taking an
'AIDS test' has long been the subject of furious debate.
The impact of the life or lives of the people who do
take the test - if it comes back positive - is incalcula-
ble, since mv is still largely associated with surefire
death.
The debate about the HIV antibody test had been
long, complex and anguished. No single diagnostic
test in the history of modern medicine has had such
a momentous impact on the lives of the individuals
who rely on it. Since the beginning of the AIDS crisis,
people have had very dramatic responses to the test
- lapsing into severe chronic depression and anxiety,
quitting, or losing their jobs, taking very toxic medi-
cations such as AZT and ddI, getting divorced, having
abortions, taking their lives and sometimes even other
people's lives, - all based, not on diagnosis of AIDS,
but merely a positive antibody test.
Given that the test holds such power, its flaws and
shortcomings are extremely significant. Unfortunately,
it is only now that this immensely important subject is
being investigated.
An Australian research team has published a review
article in the June 11 issue of Biofl'echnology (E.
Papadopoulos-Eleopulos, V. Turner & J. Papadimitri-
ou, 1993, 'Is a Positive Western Blot Proof of HIV
Infection?', Vol. 11, pp 696-707) that calls into ques-
tion the accuracy of even the most accurate of the HIV
antibody tests, the so-called Western Blot test, which is
said to be over 98% accurate. They state that the test is
seriously flawed on several counts: that it is not stan-
dardized, that it cross reacts with non-HIV proteins,
and that ultimately, it is not reliable proof of actual
infection with mv.
Through their sharp critique of the methods oftest-
ing for HIV, the authors raise astonishing points about
the virus itself - what is known and not known, what is
seen vs. what is assumed. In the end, we get a dazzling
insight into the precarious and fickle world of retrovi-
343
rology. How infinitely complex it is, compared to the
simple terms in which we've come to think of it.
The article, entitled 'Is a Positive Western Blot
Proof of HIV Infection?' was published in the June
11 issue of Biofl'echnology a science journal put out
by Nature Publishing. The Australian researchers,
Eleni Papadopoulous-Eleopulos, Valendar F. Turner
and John M. Papadimitriou, conclude that ' ... the
use of antibody tests as a diagnostic and epidemiolog-
ical tool for HIV needs to be re-appraised'. 'A posi-
tive HIV status has such profound implications', they
write, 'that no one should be required to bear this bur-
den without solid guarantees of the verity of the test
and its interpretation'.
Eleopulos and colleagues examine both HIV anti-
body tests: the enzyme-linked immunosorbent assay
(ELISA) test, the first test used to screen blood, which
costs about $50, and the Western Blot (WB) which is
used to confirm a positive result on the ELISA, and
costs closer to $100. They sum up the problems with
both tests by making four major points: The tests are
1) not standardized, meaning that different labs have
different criteria for specifying what is negative and
what is positive; 2) not reproducible, meaning the test
fails when tested against itself, and repeated tests can
be alternately positive and negative; 3) proteins that
are thought to be exclusive to mv may instead be
cellular contaminants, or debris; and 4) there is no
'gold standard' , for the HIV test. Every diagnostic test
must have a 'gold standard', and in this case it would
be HIV itself, but the authors argue, this is impossi-
ble since HIV has never been isolated in pure form
without cellular contamination. Even the Polymerase
Chain Reaction (PCR) - the one test that looks for
HIV genetic material as opposed to viral antibodies -
detects only one viral gene, the researchers argue, not
the virus in its entirety. The PCR is far more sensitive
than the WB. It costs several hundred dollars and is not
commonly used.
344
The first test developed for HIV in 1985, the ELISA
test, was developed to screen out HIV from the blood
supply. It is highly sensitive, and very nonspecific,
which means it gives a positive result easily even when
there is no HIV present. As many as four out of five
ELISA tests cannot be confirmed by Western Blot.
The ELISA is still the only test that is used in the
Third World, most notably Africa, where very alarmist
projections about HIV in the population have been
made. In the United States, no person is supposed
to receive a result that is based only on ELISA, a
test which is used primarily as a first filter for the
blood supply. Instead, a positive test is given when
a person has one or two positive ELISA tests, which
are them confirmed by a single WB test. However,
the BiolTechnology article details many cases of the
test being inaccurate despite all these steps being tak-
en. Often, a second WB contradicts the first one. For
example, they cite data from a mass testing done by the
U.S. Military which contained some startling findings.
There were 4000 people who had two positive ELISAs
followed by a negative WB (note: all of those 4000
would be called HIV positive in Africa and HIV neg-
ative in the West). But perhaps more startlingly, there
were 80 cases of people who had two positive ELISAs
and a positive Western Blot, followed by a negative
follow-up Western Blot. In other words, those 80 peo-
ple, had they not been a part of this particular, scrupu-
lous study, would have been told they were HIV posi-
tive, since a single positive WB is all that is required,
but in fact they were negative. How many other people
who have been told, based on a single positive WB that
they are positive, are really negative?
Though it is not necessary to perform a test in order
to diagnose AIDS, a positive test does confirm, accord-
ing to Centers for Disease Control (CDC) regulations,
an AIDS diagnosis. In the absence of a positive HIV
test, conditions get treated for what they are; with a
positive result, they all get labeled AIDS. The defini-
tion of AIDS includes some 25-30 different symptoms
that occur in the presence of a positive HIV antibody
test. What few people are aware of, however, is that the
test is not an absolute, and there is a broad gray area
that many people may fall into. For instance, many
people fall into a never mentioned category technical-
ly called WBI, or Western Blot Indeterminate, which
means they hover between a positive and a negative
result, and whether they are told they are positive or
negative may depend on which lab tests their blood.
In both tests, ELISA and Western Blot, a patient's
blood is added to an antigen preparation and suppos-
edly, ifHIV antibodies are present, they will react with
the HIV proteins. But the BiolTechnology paper raises
some disturbing points about the difficulty of develop-
ing a truly accurate diagnostic test, particularly when
the microbe in question, HIV, is barely present in the
blood.
HIV has been notoriously difficult to isolate, which
is defined by Eleopulos as 'separating the virus from
everything else'. Consequently, The Western Blot
detects patterns of proteins thought to be specific to
HIV These are specified as 'p' for protein, followed
by a number which represents a molecular weight. HIV
is recognized by proteins p24, p17, gp41, gp120, etc.
These proteins have been said to be exclusive to HIV,
but Eleopulos and colleagues demonstrate that they
are not. One protein in particular, p24, is 'currently
believed to be synonymous with HIV isolation and
viremia'. But Eleopulos and colleagues detected p24
antibodies in a number of people who do not have
HIV, including 13% of healthy patients with general-
ized warts, one out of every 150 healthy people with no
afflictions, and 41 % of patients with multiple sclerosis,
among others. Conversely, p24 is not found in all HIV
or even AIDS patients, they point out.
A major problem with the Western Blot that has
never been assessed before is the fact that it cross
reacts with other microbes. People who have certain
auto- immune disorders, lupus and rheumatoid arthritis
for instance, have been known to test positive for HIV
even though they are not infected. The BiolTechnology
paper demonstrates how the test can cross react with
other microbes, including ones as common as malaria
and TB.
Eleopulos, Turner and Papadimitriou report on a
paper that examined a tribe of Amazonian Indians who
have no contact with anybody outside their tribe and
who have no incidence of AIDS, yet, 3.3-13.3% were
HIV positive by Western Blot. 'The above data', the
authors speculated, 'means either that HIV is not caus-
ing AIDS' .. .'or ' ... the HIV antibody tests are
non-specific' .
The study also details the fact that people with
severely depressed immune systems, hemophiliacs and
blood transfusion recipients for example, may test pos-
itive because they have so many foreign proteins and
antigens in their blood. Receiving foreign cells or pro-
teins from another person has been shown to cause
immume disruption regardless of whether or not HIV
is present.
The BiolTechnology paper specifies the vastly dif-
ferent criteria used by different institutions to interpret

the WB test, and point out that an antibody test can
only be meaningful when it is standardized, that is,
'when a given test result had the same meaning in all
patients, in all laboratories, in all countries'. They sent
one blood sample to 19 different laboratories, which
all showed it to be HIV positive, but with wildly dif-
ferent band patterns. (With WB, individual proteins
are recognized visually as colored bands). In another
instance, a blood sample was sent 89 times to three
laboratories; one pattern was reported 64 times, anoth-
er pattern 19 times, yet another pattern 4 times, and
once the sample tested negative.
The Food and Drug Administration (FDA) has the
most stringent criteria for the WB interpretation, fol-
lowed by the American Red Cross, and the Consor-
tium for Retrovirus Serology Standardization (CRSS).
According to the BiolTechnology paper, less than 50%
of all AIDS patients have a positive WB when the FDA
criteria are used. If the criteria of the CRSS are used,
the percentage of positives goes up to 79%.
I asked a few scientists to comment on the Eleop-
ulos paper, all of them signatories in the Group For
The Scientific Reappraisal of the HIV Hypothesis.
Dr. Charlie Thomas, a former Harvard biologist, and
founder of the Group for the Scientific Reappraisal of
the HIV Hypothesis, said he thought the Eleopolus
paper was 'absolutely stupendous'. 'I think the HIV
test has now been substantially challenged, and should
be withdrawn from the market until these questions are
resolved', he said.
Dr. Robert Root-Bernstein, a critic of AIDS scien-
tific literature and author of Rethinking AIDS (FreeP-
ress) was more reserved. 'I agree to a point - just
because you have a positive WB doesn't mean you
have HIV. But that doesn't mean you can throw out the
whole thing either. What I'm seeing when I read the
literature is that almost everybody who has antibody
by WB has a positive PCR or co- culture if they go on
to take those tests. And those are the papers that are
ignored in here. This is a point on which I disagree
with Peter Duesberg [who says that antibodies mean
the infection is defeated]. I'm more than willing to
admit that there are people who don't have virus but
they have the antibody, and theoretically that could be
a lot of people, but if you look at the studies that have
been done, it appears that almost everybody who has
the antibody actually is infected and does have a low
level infection. I think that a positive HIV test is still a
strong predictor for getting AIDS' .
Root-Bernstein, in his book, has put forth that
AIDS is a multi-factorial syndrome, or possibly an
345
auto-immune disease. 'To be real convincing' , he con-
tinues, 'Eleopulos and colleagues would have to come
up with a more accurate marker for AIDS. I'm still an
agnostic about whether or not HIV is the cause, but it
certainly is a good marker for it' .
Dr. Peter Duesberg counters, 'If a virus is to be
claimed for a disease you want to see the virus, not
an antibody against the virus. An antibody is not a
virus and it's not a predictor for disease, it is only an
indication that the virus has been neutralized, in some
cases a long time ago. If you try to diagnose polio, hep-
atitis, measles you can find the virus, you don't have
to mess around with antibodies. Only in AIDS do we
focus on the antibody'. Professor Alfred Hassig, who
was head of the Swiss Red Cross Blood Transfusion
Service for thirty seven years, commented. 'I think she
[Eleopulos] is perfectly right. Every test in serology,
immunology has false positives and false negatives.
But Western Blot had been taken as a holy measure,
and that is very unfortunate for the person getting the
result'. Root-Bernstein feels differently. 'By the time
you've got symptoms, does it really matter whether
you've got HIV or not? You still have to be treated for
AIDS. The big issue there is what we think is causing
AIDS. I tell people to go see Dr. Joe Sonnabend [a
New York AIDS physician]; he won't treat the HIV,
he'll treat everything else. I think that's perfectly rea-
sonable.
The other thing is, I've got a file that keeps grow-
ing - that there are people who are positive by ELISA,
Western Blot and PCR, who have low T cell counts,
and they lose all those things. They sero-convert to
HIV-negative by all tests, and their T cells stabilize or
go up. They're usually people who alter their lifestyle.
It's important to point out is that even if you are pos-
itive that dosen't mean you will get AIDS. At least in
a small percentage of cases, people can spontaneous-
ly eliminate an HIV infection'. The suggestion that
people 'change their lifestyles', is one of the most
inflammatory, frowned upon ideas in the AIDS debate.
I asked Root-Bernstein to be specific.
'All the cases I've read are in one of two groups.
Either limited exposure, like a girlfriend of a hemophil-
iac who leaves him or they start practicing safe sex, or
they're gay men or IV drug users who quit. Quit the
drugs or for gay men find a stable sexual partner and
practice safe sex. As I said in my book, I don't think
there's anybody who gets AIDS from a single exposure
to HIV. Even if you look at the transfusion cases, most
of those people got 20 units of blood. Most people are
constantly reinfected'.
346
'I think she [Eleopulos] makes some very excel-
lent, important points', says Dr. Peter Duesberg ofUe
Berkeley, famous for his views that HIV doesn't cause
AIDS. 'She is correct to say that it is not chemically
pure, that it is contaminated with human cellular pro-
teins, and who knows what effect that has on the test
result' .
Duesberg, unlike Root- Bernstein, can see no value
in the HIV antibody test, accurate or not. 'With all
other viruses the antibody tests, if they are done at all,
are only there to show that you are immunized, you
don't need another shot' , says Duesberg.
When asked what the response in the scientific com-
munity to the BiolTechnology paper has been, Harvey
Bialy, the editor of the study and scientific editor of
BiolTechnology, said, 'essentially none. I expected let-
ters denouncing it, but I haven't received a single one'.
'None of the testing companies have withdrawn their
advertising', Bialy said with a laugh.
'It sort of makes no difference what the truth is
because the antigen test for the p24 antigen has been
thoroughly discredited and is still used'. 'In this field
[AIDS] what the facts are is irrelevant', says Bialy.
'All people will say is that by pointing out that the
antibody test may not be accurate you're encouraging
people not to use condoms. No matter what you say
which legitimately criticizes the science of AIDS, the
accusation is always that- you're encouraging people
not to use condoms'. I called Australia to speak to the
research team, but they had been besieged by interview
requests, though interestingly, not a single one from the
American media.
The debate about this paper will probably be pro-
tracted. Some will denounce it as nonsense, others will
follow its leads. But it certainly ought to have a sober-
ing effect on HIV testing and the hysteria that goes
with it. 'Why does this paper matter?' Root-Bernstein
asks rhetorically, 'It matters to all the people who test
positive for HIV by Western Blot and assume they have
AIDS and are going to die, or that they have to take
AZT. She [Eleopulos] has convinced me that the tests
are not as good as most people think they are'.
P.H. Duesberg (ed.), AIDS: Virus- or Drug Induced?, 347-358, 1996.
© 1996 Kluwer Academic Publishers.
Cry, beloved country
How Africa became the victim of a non-existent epidemic of HIVIAIDS
Neville Hodgkinson *
Global Retreat Centre, Brahma Kumaris World Spiritual University, Oxford, UK
It has become increasingly clear during the 1990s that
in prosperous, developed countries, AIDS is remain-
ing almost exclusively confined to people with clear-
ly defined risks to their immune system regardless of
HIV. These risks include heavy drug use, promiscuous
receptive anal intercourse, or, as with the injections
given to patients with haemophilia before the arrival
of high purity Factor 8, repeated exposure to other
people's blood. In Britain, out of a cumulative total of
6929 cases of AIDS in the first ten years of the epi-
demic, only 63 were in heterosexuals who were not
obvious members of one of the known risk groups. In
the United States, a 1992 National Research Council
report found that many geographical areas and popu-
lation groups were virtually untouched by AIDS, and
would probably remain so.
These facts do not fit the theory that the world is in
the grip of a deadly new infectious disease, putting at
risk almost all sexually active people. However, that
theory appeared to gain support from reports that mil-
lions of Africans are HIV-infected, and that hundreds
of thousands are dying from the disease, with men and
women equally at risk. What is happening to Africa
today, it was argued, should serve as a warning of
what may happen to the rest of the world tomorrow,
even if it takes longer than had been expected.
In March, 1993, a television documentary was
shown in Britain which challenged the by now conven-
tional view of Africa as a land devastated by AIDS. It
was based on a two-month investigation in Uganda and
the Ivory Coast, and was made by Meditel, an inde-
pendent company that had previously aired the views
of scientists who argue HIV is not the cause of AIDS.
It concluded that Africa was not in the grip of an AIDS
• The author is a fonner medical and science correspondent of
The Sunday Times, London.
347
epidemic, but that panic over the disease was leading
to a tragic di version of resources from genuine medical
needs.
The film crew were accompanied during their
inquiries by Dr. Harvey Bialy, a scientist with long
experience of Africa, whom I interviewed at the time
for an article in The Sunday Times. He had concluded
there was 'absolutely no believable, persuasive evi-
dence that Africa is in the midst of a new epidemic of
infectious immuno-deficiency'. But because interna-
tional funds were available for AIDS and HIV work,
politicians and health workers had an incentive to clas-
sify traditional African diseases as AIDS. The problem
was compounded by the fact that HIV testing was fre-
quently misleading in Africa, as the tests reacted to
antibodies to other diseases, producing high rates of
false positives.
Bialy, a microbiologist working as research editor
of Bioffechnology magazine, has been visiting Africa
since 1975, and has spent a total of eight years work-
ing there. On the face of it, this gave him considerably
more authority than the large numbers of western sci-
entists and other workers whose first exposure to the
continent was brought about by AIDS.
He was angry that so many damaging claims had
been made about AIDS in Africa on the basis of so lit-
tle science. 'The only utterly new phenomenon I have
seen is in the drug-abusing prostitutes in Abidjan in
the Ivory Coast', he told me. 'These girls come from
Ghana, from families of prostitutes who are brought
in by the busload. They have been doing this for gen-
erations, and never became sick until now. What is
new is that these girls are addicted to viciously adul-
terated, smokeable heroin and cocaine. It completely
destroys them. They look exactly like the inner-city
crack-addicted prostitutes of the United States.'
348
'Otherwise, I have seen malaria, tuberculosis, diar-
rhoeal diseases, which arguably have got more severe;
but by all the laws of scientific reasoning this is caused
by the general economic decline in these countries, the
decline of health care and the development of drug-
resistant strains. All these things can explain exactly
what is going on much more efficiently and persuasi ve-
ly, and to much greater good for the public health, than
saying the diseases are being made worse by HIV' .
Our four-column story about these and other doubts,
headlined 'Epidemic of AIDS in Africa 'a tragic myth',
brought a crop of contrary assertions, but no evidence
in rebuttal. My confidence in the story was further
boosted by an astonishing statement Bialy had made
about the HIV te~t.
Bioffechnoiogy had a paper in press, he told me,
which did more than highlight a problem with false
positives: it challenged the very basis of the test as
indicating the presence of a specific virus, arguing that
it had never been validated against the accepted 'gold
standard' for a diagnostic test, isolation of the virus
itself.
I found this hard to take in, and did not pursue
the story further immediately. But over subsequent
weeks, I studied the paper concerned and corresponded
with the main author, Eleni Papadopulos-Eleopulos, a
biophysicist at the Royal Perth Hospital. To my con-
tinuing astonishment I found that there was indeed a
mass of evidence, pulled together in Eleopulos's enor-
mous review article, that what had come to be called
'the AIDS test' was scientifically invalid. The proteins
detected by the test kits were not specific to a unique
retrovirus. Positive results were produced in people
whose immune systems had been activated by a wide
variety of conditions, including tuberculosis, multiple
sclerosis, malaria, malnutrition, and even a course of
flujabs. Patients with AIDS, and promiscuous gay men
leading lives likely to expose their immune systems to
multiple challenges, were certainly much more likely
to test positive than healthy Americans, but for reasons
that need not have anything to do with a deadly new
virus.
The possible implications of the Bioffechnoiogy
article for an understanding of AIDS in Africa were
clearly enormous. African countries were those where
the tests might be at their most meaningless, because
of the widespread ill-health caused by malnutrition and
associated chronic diseases. Had an entire continent
been panicked by western scientists into believing it
was in the grip of a deadly epidemic, on the basis
of a test that had never been shown to be valid for the
retrovirus whose presence it was claimed to detect?
I faxed the article to four virus experts in case some
glaring error invalidating its reasoning had been missed
by Bioffechnoiogy. One did not reply, and another pre-
ferred not to comment. A third, Dr. Philip Mortimer, of
the Virus Reference Division at Britain's Central Public
Health Laboratory, wrote a courteous reply acknowl-
edging that the article 'does make some fair points
about the weakness of the western blot test when it is
used incautiously and without follow-up'. He added,
however, that 'the situation it describes is not typi-
cal of this country where initial positive serological
(antibody) screening tests are confirmed by (i) fur-
ther investigations, usually a combination of different
ELISA assays but sometimes including Western Blot
and (ii) a test of a follow-up specimen. Only if the
positive reactions on both specimens are confirmed,
usually in a reference laboratory, is a positive report
issued'. Perhaps this more stringent procedure helped
to explain why Britain had only some 23 000 sero-
positive people, compared with an estimated 1 m in
the United States and multi-millions in Africa. But
Eleopulos et ai. had not just criticised the Western Blot
test. They had cited evidence indicating that the ELISA
test might be equally meaningless. In Russia in 1990,
for example, out of 20 000 positive screening tests,
only 112 were confirmed using western blot. A similar
study in 1991 confirmed only 66 out of approximately
30 000 positive test results. Clearly, by using multiple
tests giving very different results, false positives would
be greatly reduced. But this still did not answer Eleop-
ulos's charge that there was nothing in the literature to
indicate why any of the tests should be considered reli-
able as indicating the presence of a specific retrovirus.
Besides, even if the damage done by false positives
was being reduced in the UK by repeated testing, that
was no comfort with regard to the situation in Africa,
where because of cost considerations, most HIV diag-
noses were being made on the basis of a single test.
Dr. Mortimer also commented that diagnostic capa-
bility had recently been advanced by the introduction
of a commercial polymerase chain reaction assay for
detecting minute quantities of HIV genetic materi-
al.
'Comparison of results using this procedure with
those obtained by antibody tests show a very close
correlation confirming the reliability of HIV antibody
tests' , he wrote. However, as the Bioffechnoiogy paper
pointed out, this correlation might be the result of some
quite different cause common to both the PCR test

and the antibody test. PCR signalled the presence of
only a small stretch of genetic material; perhaps it was
picking up the presence of a sequence made detectable
by the same stimulus as that which caused a person to
test antibody-positive, a stimulus which need not have
anything to do with 'HIV'. The Bioffechnology paper
cited evidence in support of this idea. For example,
a positive PCR reverted to negative when exposure
to risk factors was discontinued; and monocytes from
HIV-positive patients in which no HIV DNA could
be detected, even by PCR, became positive for HIV
RNA after immune activation by co-cultivation with
activated T-cells.
The fourth virus expert was Professor Robin Weiss,
head of the Chester Beatty Laboratories at the Institute
of Cancer Research, London, who with Dr. Richard
Tedder, a virologist at the Middlesex Hospital in Lon-
don, developed and patented Britain's first HIV test
in conjunction with the Wellcome drug company. Dr.
Weiss took the trouble to write a two-page letter con-
cerning the Bioffechnology paper. His tone was set
in the first paragraph: 'It is the sort of paper I would
have stopped reading by paragraph 5 if you hadn't
requested an opinion'. Later, he commented: 'Sorry,
if the authors were my students, I'd mark this essay
B-minus. Ofthe 1000 or so papers on HIV/AIDS that
must have been published in the last six months, I'd
put this in the bottom 10% for being worth report-
ing' . He acknowledged that the paper might have had
some merit if it had been published around 198617, as
'there were serious difficulties and much variation in
assessing Western Blot data, and some of the ELISA
tests were still giving false positives'. But since then,
he argued, the tests had been greatly improved because
they used HIV antigens produced in bacteria by recom-
binant DNA technology, rather than grown from sera
taken from AIDS patients.
It seemed to me that he had not answered the cen-
tral complaint, that no one had ever established that
the proteins held to indicate the active presence of
HIV really are related to the virus in people who test
positive, as opposed to other possibilities raised by
the Bioffechnology authors. I wrote back along those
lines. Robin Weiss responded with a short, unrefer-
enced assertion: 'As I wrote, that might have been a
valid argument six years ago, but not today as the pro-
teins have been specific for some years'.
On August 1, 1993, the Editor ran our most challeng-
ing story to date across the top of the front page. The
349
headline read: 'New Doubts Over AIDS Infections As
HIV Test Declared Invalid'. The story began:
The 'AIDS test' is scientifically invalid and inca-
pable of determining whether people are really
infected with HIV, according to a new report by a
team of Australian scientists who have conducted
the first extensive review of research surrounding
the test.
Doctors should think again about its use, say the
authors. 'A positive HIV status has such profound
implications that nobody should be required to bear
this burden without solid guarantees ofthe verity of
the test and its interpretation', they conclude. The
findings, likely to cause intense debate in the med-
ical fraternity and anguish for many HIV-positive
people, are contained in an article published by the
respected science journal, Bioffechnology. Many
people who appear to be infected by HIV, say the
researchers, can be suffering from other conditions
such as malaria or malnutrition that produce a pos-
itive result in the test. Even flu jabs can produce
the same effect. As a result, predictions by the
World Health Organisation that millions are set to
die because of being HIV-positive may be wildly
inaccurate. The paper also lends powerful support
to the theory, held by growing numbers of scien-
tists, that HIV is not the true cause of AIDS. One of
its authors, Eleni Eleopulous, a biophysicist at the
Royal Perth Hospital, said this weekend: 'There is
no proof that people labelled as 'HIV-positive' are
infected with such a retrovirus. We should really
question the role of HIV in the causation of AIDS.'
The claims were so at odds with conventional think-
ing on this enormously important subject that I had
been nervous of writing the article, having already had
to cope with huge waves of fierce criticism and com-
ment in relation to previous articles questioning the
HIV theory of AIDS. But this time, there was hardly
a word of protest, let alone any arguments of rebuttal.
No scientific papers to validate the tests. And no com-
ment elsewhere in the media. We were being privately
'rubbished' by the AIDS experts to whom specialist
writers turn in such cases. But it seemed their case was
too weak for them to wish to state it publicly.
This gave me the push I needed to undertake a ven-
ture that the Editor had long since approved, namely, to
mount our own investigation of AIDS in Africa. Was
the situation as described by Harvey Bialy in Uganda
and Ivory Coast also true of other central African coun-
tries? On August 18, armed with the Bioffechnology
350
paper, I flew to Nairobi, Kenya and began to make
inquiries.
It soon became clear to me that because of the idea
that HIV was lethal and rampant, there was a con-
sensus belief that one could hardly be too alarmist in
public pronouncements about Aids. The Kenya Times,
for example, earlier that year had reported estimates
by the Kenya Medical Research Institute (KEMRI)
that the country had about 100 000 AIDS cases, and
about one million people 'who have the AIDS-causing
virus'. It added that 'once a person is infected with the
killer disease, his next step is definitely death'. But
the figures were impressionistic. They were put out by
researchers who had been alarmed to find that about
half of the people going to various hospitals for gener-
al medical reasons were testing positive. Perhaps the
whole edifice of fear and concern sprang from a sci-
entifically unvalidated test, and a misinterpretation of
the meaning of a positive test result.
According to KEMRI's Dr George Gachihi, 'when
you see a young man or woman die after a short illness,
chances are that he succumbed to the AIDS disease'.
It was that perspective which led the Kenya Times
to report that 'thousands of Kenyans die each year
from AIDS, though the certificates always indicate that
they died from other causes'. When one looked at the
figures through the perspective of the Bio/l'echnology
critique, however, there was no longer any need to
see the deaths as other than from the stated causes.
Similarly, despite stories about hospitals being filled
to overflowing with AIDS victims, when I visited the
huge Kenyatta National Hospital in Nairobi I found
that although there was immense overcrowding, only
a handful of patients had been admitted with an AIDS
diagnosis.
I also found that political factors were playing a
part. Kenya had lost an estimated $300 m in desperate-
ly needed foreign currency in November 1991, when
the industrialised world tried to force political and eco-
nomic reform on the country by cutting aid. A recent
crisis announcement on AIDS by the country's health
minister was seen within the international aid commu-
nity as an attempt to win back donor sympathy and
funds, according to the journal Africa Confidential.
'A far-from-veiled theory in circulation says figures
which show AIDS spiralling out of control have been
massaged to extract sympathy', the journal said.
'In stark contrast to the recent past, when AIDS
was a banned subject to protect the tourist industry, the
press has started reporting ever more startling increas-
es in AIDS cases and newspapers are competing for
horror stories of AIDS deaths'.
It did seem to be true that doctors were reporting
growing numbers of AIDS cases, especially among
prostitutes. But in this latter group, the actual cause of
death was often unknown. When a prostitute who had
tested HIV-positive subsequently disappeared, it was
assumed that she had gone back to her home town to die
of AIDS. I also found that researchers knew nothing of
the doubts over the HIV test, and had not established
the extent to which the increase in cases of immune
system dysfunction was genuinely the result of a new
virus, as opposed to a consequence of an intensifica-
tion in long-established threats to health. According to
some observers, poverty had driven millions of wom-
en into prostitution, and young African males had also
been drawn into the trade.
There was nothing to support the apocalyptic vision
of Africa's future espoused by the World Health Organ-
isation on the basis of its HIV statistics. I found in
Kenya as elsewhere that the statistics were often based
on small clinical surveys, with the results then writ
large by computer to form an estimate for the coun-
try as a whole - and all this using a test which the
Bio/l'echnology paper had shown to be unvalidated and
probably invalid. One WHO official told me: 'AIDS
is there. No doubt about it. And it is widespread and
increasing. My colleagues in the other countries can
tell you the same'. But she added frankly: 'If you
come with this postulate that there are a lot of false
HlV-positives, it is very difficult to tell'.
The first story I filed back to The Sunday Times focused
on the experience of a remarkable doctor whom I met
in Nairobi, Father Angelo D' Agostino. Then aged 67,
he was a former surgeon who trained as a Jesuit priest
and became a professor of psychiatry in Washington
before going to Africa ten years previously. In 1992
he had founded Nyumbani, a hospice for abandoned
and orphaned HlV-positive children, after finding that
because of the panic over AIDS, nowhere else would
take them in. Regardless of HIV, there were good rea-
sons why the foundlings, whose plight he learned of
through work with a local Barnardo's home, should
often perish. Abandoned by their shocked and stig-
matised HlV-positive mothers, the children died of
multiple infections, malnutrition, and misery.
'People think a positive test means no hope, so the
children are relegated to the back wards of hospitals
which have no resources, and they die', D' Agostino
said. 'They are very sick when they come to us. Usu-

ally they are depressed, withdrawn, and silent. Some
have been in very poor conditions. But as a result of
their care here, they put on weight, recover from their
infections, and thrive. Hygiene is excellent, that they
wouldn't have in the slums they have usually been
living in. Nutrition is very good: they get vitamin
supplements, cod liver oil, greens every day, plenty
of protein. They are really flourishing. Even one that
came in with TB is doing better now' .
A year on from opening the hospice, 0' Agostino
was puzzled. Elsewhere in Kenya and across sub-
Saharan Africa, according to WHO, tens of thousands
of children were dying because of HIV, usually in their
first year. But most of the Nyumbani babies were thriv-
ing, as I knew from spending a couple of hours there
with several of them crawling all over me. Only one
of the first 45 children had been lost - a six-week-old
who was so sick when she came that she had to go
to hospital almost immediately, and died two weeks
later.
In an extensive interview, 0' Agostino told me: 'I'm
a physician, and I bought the theory that HIV is the
cause of AIDS. But there are not a lot of things I would
die for, and certainly not a scientific hypothesis. In fact,
I would welcome with open arms any proof that these
children will be free of disease' .
'It is surprising. We expected more deaths, and
a lot more serious illness. According to most predic-
tions, the children should have died within two to three
months of coming to us. Instead, we have now had to
set up a nursery school, which I didn't think would
be needed, and I'm planning to negotiate their entry
into primary school'. He had also been preparing to
establish group therapy for the mothers and other care-
givers, to deal with their grief at the loss of the children.
Instead, the only losses were happy ones: some of the
children became HIV-negative, and were taken back
by relatives or ordinary children's homes. Even those
who persistently tested positive were staying well. 'I
don't have any explanation for it. Will they be alive
this time next year? I have no reason to doubt it: they
are healthy'.
As my travels progressed, through Zambia, Zim-
babwe and Tanzania, it became more and more obvious
that there were great uncertainties over the extent of
African AIDS. The belief that there was an epidem-
ic had taken root in many people's minds, and some
unexpected or unexplained deaths tended to be seen
in the light of this belief. But was there really a new,
clearly identifiable clinical condition?
351
In Lusaka, Zambia, I was told by Guy Scott, an MP
and former cabinet minister, that the disease threatens
to orphan 2 m children, and to take the lives of large
numbers of staff in companies, public utilities, and
government. 'It is ripping through the system. It is an
absolute disaster', he said. Screening surveys conduct-
ed in late 1992 had found that as many as four out of
ten sexually active people were testing HIV-positive,
spurring the government into launching a new anti-
AIDS campaign.
But several doctors at the University Teaching Hos-
pital in Lusaka had a different view. They responded
warmly to the BiolTechnology paper, finding that it
reflected and helped to explain their own experience.
They had been particularly puzzled by an enormous
gap between reports of people testing HIV-positive,
and the number of people reported as falling ill with
AIDS - fewer than 1000 a year, in a nation of 8 m
people.
Dr. Franci Kasolo, head of virology, said work in
his department suggested the HIV figures could not
be taken at face value. 'We have found a big problem
with false positives', he said. 'When we repeat the
tests, there are a lot of disparities in the results. A test
kit from one manufacturer behaves differently from
another's'. The conclusion was that 'most ofourresults
are more or less compromised'.
Most of the country's 80 testing centres were unable
to afford confirmatory Western Blot testing after an
initial positive ELISA. And in any case, the Western
Blot produced widely differing results. A third, rapid
test had been shown to produce up to 40% false positive
results.
Dr. Wilfrid Boayue, the WHO representative in
Zambia, said the recent surveys had shown such a big
increase in positive results compared with six to seven
years previously, when the proportion was only about
5 to 8%, that he shared concern that the country was in
the grip of an HIV epidemic. Kasolo, however, thought
changes in the type of test kit used might contribute to
the changing picture. He had a lot of experience with
this, because international aid for developing countries
is often tied to use of materials provided by the donor
nations, and the donors keep changing.
'Most of the kits are supplied by the donors. If one
decides not to provide funds any more, we move to
another who will, and the kits come from that country
instead. So the kits vary a lot: reporting can be high
or low, depending on the kit. We have had individuals
tested in one laboratory, and told they are positive,
who move on to another, where they are negative. It
352
is important that we address the whole issue of HIV
in Africa scientifically. There is something going on
that we do not understand'. Dr. Sitali Maswenyeho, a
paediatrician at the University Teaching Hospital and
former fellow in AIDS research at the University of
Miami, said he had long argued against the HIV test.
'It's non-specific', he said. 'The test itself is killing a
lot of people here. The stigma is doing the damage.
We have malnutrition, bad water, poor sanitation, and
when on top of that you are told you have an incurable
disease, that really cuts off people's lives'.
Despite concerns over the validity of the HIV test,
the presence of a severe form of immune system failure,
affecting mainly sexually active people, was widely
acknowledged. But there was argument over its caus-
es. Kasolo maintained that a variety of sexually trans-
mitted infections might be responsible, a view shared
by many older Zambians. Others felt it might be asso-
ciated with over-use of aphrodisiac drugs, made from
plant sources.
David Chipanta, 22, an HIV-positive man helping
with the work of an AIDS education and counselling
organisation, said: 'People in the villages tell us it
is not new, but that it has become worse because of
promiscuity'. Despite disagreeing with that view - he
argued that promiscuity was itself nothing new - he
supported the challenge to HIV testing.
In Zimbabwe, health authorities were convinced
that AIDS was a real threat, but Dr. Timothy Stamps,
the minister of health and child welfare, was also con-
cerned that WHO and the 'AIDS industry' had fostered
a damaging epidemic of what he called 'HIV-itis' in
Africa. 'My basic worry is that it's distracting money
and attention and personnel from the known problems
such as malaria, tuberculosis, sexually transmitted dis-
eases and safe motherhood', he said. He was particu-
larly disturbed by WHO advice discouraging women
who had tested HIV-positive from breast-feeding their
babies.
Despite clear evidence confirming the thesis that
the HIV story was gravely flawed, it was hard for me
to be sure, when faced with widely differing views
among those I met, whether or not some new, epidem-
ic condition was afflicting Africa. But in Tanzania,
I met two medically trained charity workers whose
dramatic testimony provided the clearest evidence yet
that the continent was not engulfed by an epidemic of
AIDS - and a profound insight into how the story of
an epidemic had come about.
In mid-life, after finding they could have no chil-
dren of their own, Philippe and Evelyne Krynen trained
in France as nurses, with a specialist qualification in
tropical medicine, in order to be able to dedicate the
rest of their lives helping Third World orphans. In
1988, they travelled through central Africa looking for
a suitable place to set up a branch of the French charity
Partage, which had agreed to support them. They heard
that the remote Kagera province in northern Tanzania,
where Africa's first cases of AIDS were diagnosed as
far back as 1983, was now an epicentre of the disease,
which had orphaned thousands of children.
After a three-day journey to the province in January
1989, a tour ofthe worst-hit places conducted by a local
Lutheran bishop seemed to confirm everything they
had been told. Whole villages were being destroyed,
people were dying continuously in and around the main
township of Bukoba, and HIV testing suggested up to
half the sexually active population was infected.
Philippe, now 51, a former pilot, and Evelyne, 43, a
teacher, prepared an illustrated report on their findings,
Voyage des Krynen en Tanzanie, which was to prove a
catalyst for world interest in the social impact of AIDS
in Africa. It presented a dramatic picture: children
alone in houses emptied of adults, or abandoned into
the care of grandparents; a football team destroyed by
the disease; old people sitting alone with their dead;
black crosses painted at the entrances of AIDS-stricken
homes.
'Here, AIDS does not choose its victims among
marginal groups', they wrote. 'It touches the entire
sexually active population, men and women alike.
Extreme sexual liberty, a weak sense of hygiene and
a lack of medical and social support have made the
popUlations of these parts a particularly homogeneous
risk group'.
As I reported in The Sunday Times, it was a message
that Western medical and charitable agencies, urgently
wanting to alert people to the percei ved dangers of HIV
and AIDS, were more than ready to hear. US, French
and Belgian newspapers, magazines and television sta-
tions took up the story. Aspects of it are still being
quoted around the world by AIDS organisations.
The couple explained to me that in common with
many other Westerners who had seen the AIDS epi-
demic as a call to arms against the perils of ignorance
and promiscuity, they had felt it was almost impossible
to overstate the dangers. They helped one young vil-
lager write a letter to schoolchildren. It said so many
of his team-mates had died that 'we can't play football
any more - so behave, and you won't get the disease
like we did here'. The letter featured in pamphlets
prepared by a European Community AIDS prevention

project and was distributed widely to schools in west
Africa.
'When we came here we had the textbook knowl-
edge of AIDS in our minds' , Philippe said. 'That it is a
sexually transmitted disease; that it would be very eas-
ily transmitted in Africa because other STDs are ram-
pant; that many Africans are HIV-positive and would
get full-blown AIDS after one or two years, faster than
in Europe; and that the virus was passed from mother
to child, affecting 50% of children. This was what we
had learned from our medical studies. And the people
who showed me what was happening here reinforced
this belief. What I wrote in my journal was with 100%
bonne conscience' .
Four years on, Partage Tanzanie was now employ-
ing some 230 full-time staff, who were helping 7000
children in 15 of Kagera's villages. There were 20
nurses, a doctor, a pharmacist, a laboratory technician,
office workers and teachers; and scores of field work-
ers who had got to know the children, caring for them
at day centres, monitoring their health and ensuring
they were well fed. As a result of the increasingly inti-
mate understanding the Krynens acquired of the region
and its people, allied to the questions the couple start-
ed asking arising from their own scientific training, a
very different picture of what was going on started to
emerge compared with their first impressions.
The first clue that there might be something wrong
with the standard medical model of HIV and AIDS
came when they started to try to organise help for
children in the border villages. 'Our aim was to help
the people help their children', Evelyne said. 'But in
some of the villages we found nobody was interested
in the future, or in the kids, any more. One reason,
we thought, was that they had been told 40-50% were
infected and were going to die, and this in a con-
text where people were indeed dying a lot, because
of poverty and an upsurge in malaria'. (Anti-malarial
drugs had helped more children through to early adult-
hood, but left them still vulnerable to the disease. Pre-
viously, those who survived the illness in childhood
were more likely to have lifelong immunity).
'The young people were convinced they were going
to die anyway, so why should they think of the children
or the future. We said that even if 50% are infected,
50% are not, so let us find out which are which. Then
those who are free of the virus can think about the
future again' .
A pilot study offering HIV tests to their own staff
produced a shock: only 5% were positive, although
almost all were young and sexually active. Perhaps
353
they were unrepresentative, the Krynens thought,
because their level of education was above average.
So in 1992 they proposed a mass testing programme in
Bukwali, a village on the border with Uganda where
some of Africa's first AIDS cases had been reported
nearly ten years previously.
Encouraged by the promise that a clinic would be
established to give free treatment to anyone testing
positive, about 850 people agreed to take part - almost
the entire population aged between 18 and 60. This
time, 13.7% were found to be HIV-positive, still much
lower than the villagers had been led to believe. The
Krynens found that a single positive test could not be
relied on - repeat testing would frequently show the
same patient to be negative. The villagers may have
shown a higher rate of HIV-positives simply because
they were older, with an average age of about 42,
compared with 24 in the staff study. They had been
exposed for longer to 'whatever it is in Africa that can
so readily cause the blood to test positive', as Evelyne
put it.
'We have noticed that with the women, the more
children they have, the more likely they are to be pos-
itive. We have five HIV-positive women on our staff,
and all have children, but a stable life. It could be
because being more in contact with doctors and hospi-
tals, and taking more drugs, or even just giving birth,
causes you to accumulate reactivity to the test. It may
not have anything to do with a virus'.
The Krynens also found that when appropriate
treatment was given to villagers who became ill with
complaints such as pneumonia and fungal infections
that might have contributed to an AIDS diagnosis, they
usually recovered.
'All of a sudden you put all you have been told
about the disease in the garbage can, and try to recon-
sider', Evelyne said. 'The 15 villages we have looked
at are in the most affected area of a region that is
supposed to be ate the epicentre of AIDS in Africa.
When you listen to the people, you find they had been
shocked by some deaths where the effects on the body
were very visual, with fungus infections and skin rash-
es. But these can be secondary effects of antibiotics,
and the people who died with these conditions had all
been treated before for conditions such as bronchitis.
Nothing is sure; everything is just wind' .
Most of the first deaths reported as AIDS were in
young men trading in black-market goods in the after-
math of the Ugandan war. It started at the border, where
people were dealing in drugs as well as otqer goods,
said Philippe. 'It's true this group had money and was
354
affected with immune suppression and a wasting syn-
drome. But it was not because they had sex like rabbits
that they died. This is what was put in people's minds
by missionaries and other people, but whatever killed
them was not sexually transmitted, because they have
not killed their partners. They have not killed the pros-
titutes they were using; these girls are still prostitutes
in the same place' .
'Was it a special booze? Has it an amphetamine or
aphrodisiac? It is difficult to give more than hints, but
when you listen to the people's descriptions of those
first affected, you find they were saying they had been
poisoned. If the local people said that, for two or three
years before the word AIDS came to the region, why
don't we believe them a bit, and look at what could
have poisoned them'?
Today the couple are continuing to use the HIV
test, 'just to prove that we have to stop doing this,
that it has nothing to do with AIDS'. They are training
their field workers not to mention HIV or AIDS, but
instead to deal with any known disease they encounter
with the best treatment available, regardless of the
patient's HIV status. 'It is not known whether HIV
causes AIDS', they say in a pamphlet produced for the
team. 'It is time to come back to science and aban-
don magic thinking'. Philippe declares: 'There is no
AIDS. It is something that has been invented. There
are no epidemiological grounds for it; it doesn't exist
for us'.
If Kagera is not, after all, in the grip of an epidemic
of 'HIV disease', and if there is no AIDS, where have
the thousands of orphans come from? The answer,
say the Krynens, is that most of the children are not
orphans at all. Their final disillusionment was to dis-
cover that although many children are raised by their
grandparents, that is a long-standing cultural feature of
the region.
'The parents expatriate themselves a lot', Philippe
explains. 'They move away from the region, send-
ing a little money, returning little or never, but still
have many children in the village. They are outwardly
orphans, but rai..;ed by the grandmother or grandfather.
It has always been like this here; they may need help,
but it has nothing to do with AIDS. Polygamy is also
rampant here and they don't raise all the children. They
select very few and the others are just made and aban-
doned'. Other children are born to prostitutes, who
may spend much of the year away from the region,
working in the cities.
'You come as a European and ask: 'Who has no
mother or father?' They produce all these children,
even though they have a mother or father in another
place. We have been showri false orphans since the
beginning - children who have parents who never died,
but who will not show up any more. And when the
parent has died, nobody has been asking why. It has
nothing to do with an epidemic. Families just bring
them as orphans, and if you ask how the parents died
they will say AIDS. It is fashionable nowadays to say
that, because it brings money and support' .
'If you say your father has died in a car accident it
is bad luck, but if he has died from AIDS there is an
agency to help you. The local people have seen so many
agencies coming, called AIDS support programmes,
that they want to join this group of victims. Everybody
claims to be a victim of AIDS nowadays ... It is good
to know that this epidemic which was going to wipe
out Africa is just a big bubble of soap'.
Posters warning of the dangers of ukimwi (AIDS)
adorn the cabins of the Victoria, a steamer that ferries
passengers on the nine-hour journey from Mwanza,
on the southern shore of Lake Victoria, to Bukoba.
When the Krynens first made the journey, they found a
small town with only a handful of foreigners and few
cars. Today, as the ferry arrives, the tiny port seizes
up with vehicles, including the white Land Rovers and
Toyotas characteristic of the numerous AIDS agencies
that have flourished in much of central Africa.
'We have everybody coming here now - the World
Bank, the churches, the Red Cross, the UN Develop-
ment Programme, the African Medical Research Foun-
dation - about 17 organisations reportedly doing some-
thing for AIDS in Kagera', Philippe said. 'It brings
jobs, cars - the day there is no more AIDS, a lot of
development is going to go away'.
The Krynens work hard. They keep files on all their
donor families and careful records of how the money
is spent. Their home, a modest bungalow on a hillside
overlooking Lake Victoria, is the hub of the project,
with its own HIV-testing laboratory. All day a stream
of workers comes by to give feedback and take direc-
tions. A few children who have nowhere else to go live
in an adjoining building. With such direct, practical
help being given to suffering people, perhaps it does
not matter too much whether the children are AIDS
orphans or not. But the Krynens are angry because
false information continues to be spread to Africa and
the world.
'Africa is a market for many things, an experimen-
tal ground for many organisations and a 'good con-
science' ground for many charities', Philippe said. 'It
is very easy to 'do good' in Africa. It is so disorgan-

ised that the one who is doing the good is also the one
reporting the good he is doing. So it is a perfect field
for charity - the fake charity which is 99% of the char-
ity in Africa, charity which benefits the benefactors'.
The Krynens felt strongly about this because of their
own involvement in triggering an invasion of AIDS
agencies to Kagera. They now know that the stories
they told, of houses and villages abandoned because of
AIDS, were untrue.
'The houses that were empty were closed because
they were the second or third homes of someone in
Dar es Salaam', said Philippe. And the black crosses
painted outside homes were leftovers from a popula-
tion census, not a warning of AIDS. 'I learned this
later. I have never seen a village with no adults, where
children are like wolves in the forest. You know who is
responsible for these stories? Partly, Partage. We said
that if we did not do something very quickly, these vil-
lages would be emptied of adults and children would
be like wild animals. The stories have been printed and
reprinted, without the 'if' '.
'My medical studies led me to believe that AIDS
was devastating and the people who showed me the
situation here reinforced this belief. I jumped into this,
and made others believe it. And now I know it was not
true. But I know many more things that were not true.
Nothing was true'.
'It is terrible to consider you have done so many
things you thought worthwhile, when in fact you were
misled. It is difficult to adjust afterwards. Nobody
knows who is responsible for the first misinterpreta-
tion, but as time passes it gets bigger and bigger. These
ideas were not based on any studies; they were just
fashion. But when you are here, and you have to wit-
ness the reality of what happens in the field, you can-
not agree with any of the statements they are making
in Europe about AIDS in Africa. We discovered we
were in a full-blown lie about AIDS. Everybody par-
ticipates in this lie, willingly or not. No individual is
responsible, but it is a big scandal' .
'The world has been brainwashed about AIDS. It
has become a disease in itself, without the necessity
of having sick people any more. You don't need AIDS
patients to have an AIDS epidemic nowadays, because
what is wrong doesn't need to be proved. Nobody
checks; AIDS exists by itself' . . (4) Compassion, understanding, care and respect
'We came here to help orphans of AIDS. Now we
are facing a situation where there are no orphans and
no AIDS. We are in the heart of AIDS country. You
are talking to people who 'discovered' AIDS here, and
who now say it is a lie. We expect to have to pay for
355
what we say. It will be the price of truth'.
Articles I filed from Africa were often followed up or
reprinted in regional and national newspapers there,
after they had appeared in The Sunday Times. With so
much money and prestige at stake, this caused some
of the people I had interviewed to come under great
pressure to recant. They responded differently to these
pressures.
Father D' Agostino was upset to see the puzzlement
and hope he had expressed in relation to the survival
of his 'AIDS babies' put in the context of the wider
critique of the HIV theory of AIDS that The Sunday
Times had been airing. To the medical profession, this
is a heresy, not just a different interpretation of the
facts, and a press release he issued on September 17 on
behalf of the Children of God Relief Institute, which
runs Nyumbani, read more like a religious creed than
a comment from a scientist. It stated:
Recently, the London Sunday Times ran a long
front-page story and the Nairobi Nation an editori-
al page 'special report'. Both papers misconstrued
the facts of the unfortunate life circumstances of
the children at 'Nyumbani' in order to prove an
erroneous thesis. While this does no harm to the
children themselves, it does a grave disservice to
. the larger community because it panders to the all
too prevalent mental process of denial. This denial
only increases the universal and deadly threat of
HIV/AIDS. In order to correct these errors, we
must assert:
(1) We do believe in the' germ' theory of disease as
proposed by Louis Pasteur. This universally proven
theory is accepted by compassionate and credible
scientists worldwide.
(2) We believe that there is a virus designated
'HIV' which has been isolated and is responsible
for the fatal disease called AIDS.
(3) Since there is no cure for the ravages of the
HIV virus, we believe that the only strategy to con-
tain and prevent spreading of the disease AIDS is
for all sectors of society to -
i) join hands in creating awareness and,
ii) urging action in an appropriate manner.
for human dignity must fashion any program to
help those suffering from HIV/AIDS.
(5) We invite any party so inclined to help our
efforts to assist in alleviating the tragic plight of
those voiceless HIV/AIDS sufferers - the aban-
356
doned child.
(6) We totally disagree with any scientifically
unsubstantiable theory that denies the reality of
the causation ofthe disease HIV/AIDS.
The uncertainties Father D' Agostino had clearly
expressed in a recorded interview, as he pondered the
surprising good health of his foundlings, were now
gone, replaced by a reaffirmation of belief in the HIV
doctrine of AIDS. I knew nothing of this press release
at the time - I was still travelling through Africa, and
had not even seen the Sunday Times - and although
Father D' Agostino says he faxed a response to the arti-
cle to the newspaper's office, it was never received
there.
In fact, the first I knew of his dissatisfaction was
when I received the following letter, dated October
22, after I had written to him on my return to London
enclosing cuttings of my Africa articles.
Dear Neville,
I want to thank you for the courtesy of sending the
article appearing in the 3rd October edition and also
for the pleasant experience that we all had when you
visited Nyumbani. That being said, I must confess to
some reservations.
You and I look at the world with quite different per-
spectives. You, from that of ajournalist and myself, as
a committed medical man. Our goals are quite differ-
ent. I, after having spent at least 14 full years in the
pursuit of medical knowledge, am committed to using
that eclectic knowledge for the good of mankind. I
am not espousing any particular philosophy or theo-
ry when I attempt to enhance the body's (and mind's)
natural healing powers. That being said then, I quite
disagree with your point of view. I am trying to be
charitable in assuming that you have taken this task for
humanitarian reasons, but I must say there is a question
about that at times.
I certainly question the Sunday Times approach
to the problem because it is quite evident that they
are more interested in selling copies rather than the
pursuit of truth. They have no care for the terrible
consequences to people when they are permanently
and fatally injured by believing the misinformation
that is being peddled. A primary principle in the prac-
tice of conventional medicine is that if one cannot do
any good, at least do not do any harm. This principle
is observed only in the breach by the Sunday Times
because they are doing great harm without even con-
sidering the possibility ... and for mere gold.
Another point: I was able to fax a response to the
article but never got any sort of admission of reception
or acknowledgement. Would it be possible for you to
inquire as to whether or not they did receive my fax
and what they plan to do about it, if anything?
Finally, I want to state that this is not a personal
issue and I would look forward to your visiting us
once again, but this time, being quite open about our
stand with regard to the terrible consequences of the
infection by the HIV virus.
With all best wishes, A. D' Agostino, SJ, MD.
On October 29, I replied as follows:
Dear Father 0' Agostino,
I was greatly distressed to receive your letter of October
22 today. Firstly, because neither I nor the Letters
Editor had known anything of your sending a response
to my article of October 3; and secondly, because of
your evident distress over what you call the Sunday
Times approach to the issue of HIV and AIDS. I had
felt that my article was a straightforward description
of what you had told me and what I had observed
for myself. I also know how much both the Editor
and myself have wanted to contribute to understanding
about HIV and AIDS, and how wrong you are to allege
that we are doing harm 'for mere gold'. Have you seen
the other articles I filed? Some of the people involved in
those have subsequently come under bitter attack from
parties who feel both the truth and their own interests
have been threatened, but perhaps the difference is that
they were aware of what a contentious issue this is.
It is not possible to back away from these issues: the
point of view to which the newspaper has been giving
an airing is that immeasurable harm, including much
loss of life resulting from panic and false diagnosis, is
being done by the blind pursuit of the HIV hypothesis
against much evidence of its inadequacies. Indeed, we
quoted - accurately - Dr Timothy Stamps, Minister for
Health and Child Welfare in Zimbabwe, as saying 'the
HIV industry ... is now in my view one of the biggest
threats to health'.
Your own uncertainty was very clear when we met.
What has happened to make you write as you did? I do
apologise if you have been embroiled in a controversy
against your wishes, but the strength of feeling on this

issue should help to indicate to you that something may
be terribly wrong in the view that your profession has
currently espoused so dogmatically about the cause of
AIDS.
I thank you for your kindness in emphasising that
you do not see this as a personal issue. Please do send
a copy of your original fax to the Letters Editor, with
a copy in the post in case of further problems. Mark
the letter clearly for the Letters Editor. I should also be
grateful to receive a copy: the news desk fax, which is
nearest to me, is ....
Neither I nor the newspaper ever received that fax
from Father D' Agostino. He told me by phone, when
the issue flared up again, that he had decided against
sending it, after receiving my letter, feeling that it was
by then too late. But that did not stop him making a
statement the following January to the Independent on
Sunday, a newspaper which has been most vociferous
in Britain in promoting the official view on HIV and
AIDS and in attacking my own reporting. In it, he
condemned the 'gross distortions and quite incorrect
implication' made as a result of my interviewing him,
and declaring that he had received no acknowledge-
ment of his original fax.
I like and admire Father D' Agostino and am sad that I
caused him distress, but I feel quite sure we were right
to run the article. The quotes directly attributed to him
were taken verbatim from my recording and expressed
his observations as a human being and a doctor, as
opposed to a politician and defender of the HIV faith.
I can understand his discomfort at the sweeping front-
page headline used on the story, 'Babies give lie to
African AIDS'. There was also an unfortunate piece of
editing, that attributed more uncertainty to him than he
had expressed. The article I filed from Nairobi included
a paragraph in which I wrote: 'The suspicion is grow-
ing that many 'AIDS' cases are really old diseases giv-
en a new name, though sometimes made worse by civil
war and economic and social decline, and that people
who testHIV-positiveare not, as most have been led to
believe, the victims of a new, inevitably lethal disease' .
The edited version correctly stated that in common with
growing numbers of scientists and doctors around the
world, D' Agostino was beginning to question whether
HIV really was the killer it had been made out to be.
That was the purport of the entire interview, during
which I had told him about the BiolTechnology paper
and the reappraisal of the HIV theory of AIDS being
sought by those doctors and scientists. But the arti-
357
cle then went on to state that 'He, like them, suspects
that many 'AIDS' cases are really old diseases given a
new name .. .' etc., a suspicion I had not attributed to
him.
His statement to the Independent on Sunday, how-
ever, made it plain that he was now putting all his
doubts behind him. He said four children in his care
had since died of AIDS out of a total of 55 with HIV,
and that two or three others had AIDS. He had no
doubt, the paper reported, that children infected with
HIV would eventually succumb to AIDS.
Since my work in this field has so often shown me how
that very expectation among doctors tends to become
a self-fulfilling prophecy, I rang D' Agostino in disbe-
lief to ask him if that was really what he now thought.
Yes, he said, 'I never questioned the medical model;
the only thing I questioned was why they didn't die
at three, why they were still alive at seven. I never
questioned that they would die. I know they will suc-
cumb'. There was 'no question' in his mind that the
four had died of AIDS. In one, it had been carditis, that
refused to clear up with the most up-to-date antibiotics.
When I questioned whether that was an AIDS-defining
illness, and asked him about the other deaths, Father
D' Agostino grew angry and told me they died of HIV,
and he was a doctor, and I had no right to question his
clinical judgement.
D' Agostino told me he had come under a lot of
pressure locally, in particular through medical chan-
nels, and I do not know what other pressures he had to
bear. But they could hardly have been more intense
than those that befell the Krynens after my article
about their changed vision of AIDS in Africa. The
European Community'S AIDS Task Force, which had
previously made a star of Philippe Krynen, now dis-
owned him and cancelled a promise of funding for
Partage. There were even attempts to have the couple
thrown out of the country. They were also invited to
recant, and condemn the Sunday Times, as in a letter
received from Dr. Angus Nicoll, consultant epidemi-
ologist with Britain's Public Health Laboratory Ser-
vice, who inquired through Partage's headquarters in
France:
Further to my communication of December 20th I
have been sent the attached letter and press release
by Father D' Agostino in Kenya. As you will read
they are complaining of some misrepresentation by
the Sunday Times and are asking that the newspa-
per convey Dr. D' Agostino's views. I also attach a
358
copy of the original article ... After reading these
letters I wondered whether Mr. and Mrs. Krynen
had been fully happy with their coverage and had
had any experience like Dr D' Agostino in trying to
make a correction?
Philippe Krynen told me that he received the same let-
ter again in January. The answer suggested by such an
amazing approach, he said - though he did not actual-
ly send it - was 'questions put by the police are only
answered in the presence of our lawyer'. In fact, he
stood by and continues to stand by every word in our
article.
In February 1994, the Journal of Infectious Diseases
published the results of a study conducted in Kinshasa,
Zaire, to try to establish whether HIV infection was
associated with leprosy. About 70% of 57 leprosy
patients, and 30% of a group of 39 contacts, tested
positive according to two leading versions of ELISA.
But after laboratory investigations, it was found that
proteins from the leprosy agent were causing cross-
reactions with the 'HIV' test. When this was taken
into account, the researchers concluded that in fact
only two of the leprosy patients, and none of the con-
tacts, were HIV-infected. Testing with Western Blot
was even more misleading. It gave a positive reaction
in 85% of the patients who were negative with the
other tests. The authors, who included Harvard's Dr.
Max Essex, one of the originators of the theory that
HIV originated in Africa, pointed out that the microbe
responsible for tuberculosis is in the same family of
mycobacterial agents. They concluded that ELISA and
Western Blot tests 'may not be sufficient for HIV diag-
nosis in AIDS-endemic areas of central Africa where
prevalence of mycobacterial diseases is quite high'.
These findings are exactly in line with the Krynens'
observations, with what Father D' Agostino originally
allowed himself to see, and with the Eleopulos paper in
BiolTechnology. They go to the root of the bad science
that has misled so many into believing Africa is in the
grip of an epidemic of 'HIV disease'. The disease is
in the minds of the scientists responsible for creating
this monumental blunder, and for perpetuating it with
campaigns to discredit those who have sought to offer
an alternative perspective.
'AIDS' in Africa is a collection of illnesses, some well
known, others perhaps yet to be identified, brought
together under an artificial umbrella by their shared
ability to cause millions to give a positive result in
what has come to be known as the HIV test.
As Professor P.A.K. Addy, head of clinical micro-
biology at the University of Science and Technology
in Kumasi, Ghana, told New African magazine: 'I've
known for a long time that AIDS is not a crisis in
Africa as the world is being made to understand. But
in Africa it is very difficult to stick your neck out
and say certain things. The West came out with those
frightening statistics on AIDS in Africa because it was
unaware of certain social and clinical conditions. In
most of Africa, infectious diseases, particularly par-
asitic infections, are common. And there are other
conditions that can easily compromise or affect one's
immune system.
'The diagnosis itself, merely being told you have
AIDS, is enough to kill, and is killing people'.
I salute the Krynens, and others like them in Africa and
elsewhere, who have been prepared to risk everything
for the sake of telling the truth as they see it.
Contemporary Issues in Genetics and Evolution
1. J.F. McDonald (ed.): Transposable Elements and Evolution. 1993 ISBN 0-7923-2338-6
2. Th.A. Markow (ed.): Developmental Instability: Its Origins and Evolutionary Implications. Proceedings of
the International Conference (Tempe, Arizona, June 1993).1994 ISBN 0-7923-2678-4
3. M.R. Rose and C.E. Finch (eds.): Genetics and Evolution of Aging. 1994 ISBN 0-7923-2902-3
4. B.S. Weir (ed.): Human Identification: The Use of DNA Markers. 1995 ISBN 0-7923-3520-1
5. P.R. Duesberg (ed.): Aids: Virus- or Drug Induced? 1996 ISBN 0-7923-3552-X; Pb 0-7923-3961-4

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