BaillieÁre's Clinical Endocrinology and Metabolism

Vol. 13, No. 4, pp. 615±633, 1999

Stress and coping:

the psychoneuroimmunology of HIV/AIDS

Elizabeth G. Balbin BS
Research Associate

Gail H. Ironson* MD, PhD

Professor of Psychology and Psychiatry
University of Miami, Behavioral Medicine Program, PO Box 248185, Coral Gables, FL 33124-2070, USA

George F. Solomon{ MD
Emeritus Professor of Psychiatry at UCLA
10724 Willshire Blvd., #602 Los Angeles, CA 90024, USA

A considerable body of evidence, reviewed in this chapter, suggests that psychosocial factors
play an important role in progression of HIV infection, its morbidity and mortality.
Psychosocial in¯uences relating to faster disease progression include life-event stress, sustained
depression, denial/avoidance coping, concealment of gay identity (unless one is rejection-
sensitive), and negative expectancies. Conversely, protective psychosocial factors include
active coping, ®nding new meaning, and stress management. In studying long survivors of HIV/
AIDS, our group has found protective e€ects on health of life involvement, collaborative
relationship with doctor, emotional expression, depression (conversely), and perceived stress
(conversely). Reviewed and discussed are psychoneuroimmunological pathways by which
immune and neuroendocrine mechanisms might link psychosocial factors with health and long
survival. Finally, biological factors are also a major determinant of disease progression and
include genetics and age of the host, viral strain and virulence, medication and several immune
response factors on which psychosocial in¯uences could impact.

Key words: stress; immunity; HIV; AIDS; psychoneuroimmunology; PNI; disease progression;
HIV long-term survivors; psychology and HIV; life-change events.

The concept that susceptibility to, and course of, infectious diseases might be in¯uenced
by psychosocial factors has a very long history. The historical basis for studying the
relationship between psychological stress and the immune response has been noted
from centuries of clinical observations of individuals who became sick following stressful
situations. Thucydides in his History of the Peloponnesian War stated that despair and an
attitude of hopelessness resulted in loss of all powers of resistance to the plague. The
`father of modern medicine', Sir William Osler, is reputed to have said (about 1910) that
*To whom correspondence should be addressed. Professor Ironson is also Principal Investigator of the
NIH-funded Study `Psychology of Health and Long Survival With HIV/AIDS', RO1MH53791.
{Professor Solomon directed the NIH-funded study at UCLA.
1521±690X/00/040615+19 $12.00/00 *
c 1999 Harcourt Publishers Ltd.
616 E. G. Balbin, G. H. Ironson and G. F. Solomon

it is just as important to know what is going on in a man's head as in his chest in order to
predict the outcome of pulmonary tuberculosis. Modern research in psycho-
neuroimmunology (PNI), the ®eld concerned with brain±endocrine±immune inter-
actions and their clinical implications, a major aspect of which is the topic area of this
volume, certainly supports this old wisdom. For example, tumbling stress increased
susceptibility to the aetiological agent of tuberculosis in rabbits.1 As early as 1919,
Ishigami2 studied the mental state of patients and its relationship to the progress of
tuberculosis through changes in sugar metabolism and adrenaline secretions. A
combination of high motivation and poor academic performance predicted the
development of infectious mononucleosis, a disease caused by Epstein±Barr virus, in
West Point cadets.3 More recently, subjects given ®xed doses of a variety of cold-causing
(rhino-) viruses intranasally developed both infection and clinical colds in a dose-
response manner with increases in degree of perceived psychological stress.4
Human immunode®ciency virus (HIV) is a retrovirus that becomes incorporated
into the genome of those cells of the host possessing receptors (CD4 and others) by
which it can enter. Is infection by HIV di€erent from all the other infectious diseases,
both viral and bacterial, that seem prone to in¯uence by psychosocial factors that a€ect
immunological resistance to them? The evidence to be presented in this chapter
suggests not. Since HIV/AIDS is a disease of the immune system as well as one resisted
by the immune system, it would seem that neuroendocrinologically-in¯uenced e€ects
on immune functions might have an even greater impact on the course of AIDS than
on the course of other infectious diseases. This chapter suggests that a signi®cant
proportion of the variance in immunological and clinical course of HIV/AIDS may be
related to thus-transduced psychosocial factors.

INTRODUCTION TO HIV

Not many of us thought early in the 1980s that a decade and a half later, a small
retrovirus, which carries its genetic information as RNA rather than DNA, infecting
CD4 lymphocytes and destroying the body's immune system, would have reached
world-wide pandemic proportions. In 1993 it was estimated that more than 34 million
people world-wide had been infected with the human immunode®ciency virus.5 By
the year 2000, this number has been projected to increase to 40 million.5 Already,
about 8.4 million people world-wide, including 1.7 million children, have died of
acquired immunode®ciency syndrome (AIDS).6
Though the earliest cases of AIDS were ®rst reported in 1981, it is now evident that
cases had been occurring unrecognized for about 4 years prior to identi®cation.7 In
fact, a blood sample collected in 1959 from an African individual is believed to contain
an early strain of HIV. Evolutionary assessment suggests that the origins of the
epidemic occurred in the late 1940s. It was not until 1983 that the agent known to be
responsible for AIDS, human immunode®ciency virus, was isolated.
Although the typical course of HIV predicts the eventual development of AIDS and
death, most commonly by an opportunistic infection or neoplasm, it has become
increasingly apparent that not only can the course of infection vary widely but also so
may the ®nal outcome. In fact, there are a small percentage of individuals who
seroconvert, making antibodies to HIV proteins, re¯ecting infection, yet appear not to
progress to signi®cant immune de®ciency and its clinical consequences. There are
many factors associated with progression or lack of progression of HIV/AIDS. In this
chapter we discuss both psychological and immunological factors, their interactions,
 Psychoneuroimmunology of HIV/AIDS 617

and their impact on HIV infection and associated immune dysfunction, morbidity
and mortality.

Pathophysiology of human immunode®ciency virus (HIV)

The Centers for Disease Control (CDC) has categorized HIV infection into four
di€erent groups based on the presence or absence of disease and clinical or laboratory
®ndings. The four groups are: an acute infection, an asymptomatic infection, persistent
generalized lymphadenopathy, and, ®nally, AIDS. Shortly after exposure to HIV,
infected individuals will develop high levels of plasma HIV RNA and mount an
HIV-speci®c immune response. Although viraemic, no measureable antibodies are
found at this time. During this early phase, the virus enters and spreads throughout
the lymphoid tissues (such as the lymph nodes, spleen and tonsils), and various organs
containing lymphatic tissues (e.g. intestines) or resident macrophage cells (e.g. brain
microglia). A persistent viral replication begins, which occurs throughout the course of
the disease. Initial viraemia is partially controlled by the immune response to the virus,
particularly by CD8 cells, until eventual immune depletion occurs. After the acute
phase is over, individuals enter into what may be a prolonged asymptomatic phase
(CDC group 2). During this time the infected individual has antibodies to HIV
(seroconversion), and is asymptomatic; yet 90% of those infected experience some
form of CD4 (helper T) cell decline within 5 years.8 Because of this prolonged
asymptomatic phase, infected individuals unaware of their HIV status may unknowingly
spread the disease. The next phase (CDC group 3) is characterized by persistent
generalized lymphadenopathy, which does not occur in all individuals. As CD4 cells
drop below 500/mm3 (normal CD4 lymphocyte values range from 800 to 1200/mm3),
individuals may experience prodromial AIDS symptoms (category B, CDC 1997
de®nition (previously known as ARC) such as diarrhoea, fatigue, oral candidiasis, fever,
night sweats and weight loss). The ®nal stage (CDC group 4) is characterized by an
AIDS diagnosis. Diagnosis of AIDS can be made by a drop in CD4 counts below 200 or
by clinical manifestations of category C symptoms (1987) such as hairy leukoplakia,
pneumocystis carinii pneumonia (PCP), and Kaposi's sarcoma, non-Hodgkin's
lymphoma, or AIDS-related dementia. During this phase viraemia increases, and so
does infectivity. Before protease inhibitor drugs became widely available, it was
estimated that, from initial exposure, 30% of HIV-infected individuals would progress
to AIDS every 5 years. Within 15 years, 90% of those infected would be diagnosed with
AIDS9, and the average length of time to development of symptomatic AIDS was about
10 years.
The clinical care of HIV-infected individuals has improved dramatically over the last
decade. In fact the disease course has changed from a virtual death sentence via
progressive deterioration of the immune system to a chronic condition, within which
most individuals can live virtually normal lives. Treatment began with the introduction
of the ®rst antiretroviral agent, zidovudine (AZT) in 1987.10 With the advent of
combination therapies that include newer reverse transcriptase inhibitors and HIV-
speci®c protease inhibitors (PI), referred to as highly active antiretroviral therapy
(HAART), signi®cant further improvement has been made in delaying AIDS and
mortality.11 In fact, about 80±90% of individuals who adhere to a protease-inhibitor-
containing regimen can achieve undetectable plasma HIV viral loads over a period of
6±12 months.12 While these drugs are very successful, viral resistance may develop,
especially when doses of these complex regimens are missed. When drug resistance
618 E. G. Balbin, G. H. Ironson and G. F. Solomon

occurs, genotyping may be used to guide the choice of salvage regimen. This strategy
has led to improved selection of medications successful in reducing viral load.13

BIOLOGICAL AND IMMUNOLOGICAL FACTORS RELATED TO

DISEASE PROGRESSION

There are a variety of psychobiological di€erences associated with lack of progression

or rate of progression of HIV infection among individuals. In this section we review a
variety of biological and immune factors related to protection against HIV infection,
non-progression of HIV infection, or slower disease progression. These include: genetic
factors, constitutional factors, viral (HIV) factors and immune factors.

Genetic factors
One of the genetic factors, which plays an important part in early infection and may
delay the onset of disease, is the chemokine receptor CCR5. Chemokine receptors are
cell surface proteins that bind small polypeptides called chemokines. Interest in
chemokine receptors has increased dramatically following the recent discovery that
many of them have been implicated as co-receptors for HIV-1.14 CCR5 is a gene
marker for a necessary co-receptor binding site for HIV on monocytes/macrophages.15
Studies have shown that being homozygous for a 32-base-pair deletion in this
chemokine receptor gene protects against HIV infection. Being heterozygous for this
deletion may slow the course of the disease as compared with being homozygous for
the wild pair CCR5.16 A second genetic factor appears to be human leukocyte antigen
(HLA) phenotypes.17 Much support has been given to the fact that genes in or near the
HLA region in¯uence the rate of disease progression among HIV-1-infected individuals.
Heterozygosity of class I loci (A, B, C) is associated with delayed onset of AIDS
compared with individuals homozygous for these loci, who progress more rapidly to
AIDS.18 Additionally, the HLA class I alleles B*35 and Cw*04 are consistently
associated with rapid progression to AIDS.

Constitutional factors
Constitutional factors that have been related to HIV progression are age and gender.
Older people progress to AIDS more quickly.19 Although some studies have found
female gender to be associated with faster disease progression, large-scale studies do
not ®nd that gender a€ects rate of progression or mortality risk.20,21 Prospectively,
clinical outcomes and mortality do not di€er between male and female drug users.22
Adjusting for CD4 count, time to AIDS was similar for men and women, but women
with half the viral load of men had a similar time to AIDS.23

Viral factors ± HIV strain

Survival time may also di€er depending on the HIV-1 subtype.24 At least 10 di€erent
genetic subtypes of HIV-1 have been identi®ed (types A±J). In addition, the syncytia-
inducing (SI) phenotype is associated with faster disease progression than non-syncytia
inducing (NSI) phenotypes.25 In fact, the presence of SI HIV-1 variants independently
predicts AIDS over and above CD4 count and viral load.26 Finally, drug-resistant strains
may appear, especially with the advent of complex drug regimens and adherence
 Psychoneuroimmunology of HIV/AIDS 619

issues. Genotypying these drug-resistant strains has led to improved selection of

medication regimens and enhanced survival.13

Immune factors
Immune factors relating to disease progression include: CD4 number, CD4 activity,
viral load, CD8 cell number, CD8 cytotoxicity, natural killer cell number (NK#),
natural killer cell cytotoxicity (NKCC), activation markers such as neopterin and
b2-microglobulin presence of neutralizing antibodies and the balance between T
helper-1 cytokines, that stimulate cellular immunity, and the T helper-2 cytokines, that
stimulate humoral immunity (TH1/TH2 balance). CD4 number and viral load are the
most widely used markers of disease progression in HIV.27 Progression to AIDS-
de®ning illness is largely restricted to patients with low CD4 counts (5200/mm3) and
high viral loads (VL) (45000 copies per ml).28 Slope of CD4 decline also predicts
progression to clinical AIDS.29,30 Perneger et al31 suggested that the ratio of CD4 cells
to HIV RNA copies is also a good predictor of HIV progression. Proliferative responses
of CD4 T cells that are HIV-speci®c have been associated with control of progression as
well.32 Low T cell response induced by T cell monoclonal antibodies also has been
shown to be predictive of progression to AIDS independently of CD4 counts and viral
load.26 CD8 cells may play a key role in the defence against HIV. This sub-class of T
cells controls viral replication by direct antigen-speci®c cytolysis and by release of
soluble antiviral factors.33 Barker et al34 suggested that the di€erence in viral load of
non-progressors may be explained by the enhanced ability of CD8 cells to suppress
HIV replication. While some CD8 cells suppress HIV replication, one subset that
expresses the CD38 marker has been associated with faster disease progression.35
Anti-HIV activity of cytotoxic CD8 lymphocytes is correlated with slower progression
of HIV infection.36 Interestingly, HIV-speci®c cytotoxic T lymphocytes were detected
in 41% of individuals exposed to HIV but not infected.37 However, the role of cytotoxic
T lymphocytes (CTL) in the pathogenesis of AIDS remains uncertain. The ongoing
debate concerns whether the CTLs control the viraemia or are a mediator of CD4
depletion and progression to AIDS.38 Non-cytotoxic CD8 cell function is also
associated with lack of infection, even when exposure to HIV is evident39, and with
long survival once infection is established.40 A combination of cellular (CD8) and
humoral (neutralizing Ab) immunity may be especially e€ective in controlling
infection.41 Humoral responses to HIV envelope proteins have also been related to HIV
disease progression.42 The presence of antibodies to HIV type 2 core protein has been
related to slower disease progression.43 Neutralizing antibodies are positively
associated with CD4 counts and T cell function in long-term AIDS-free infection.44
The level of complement activation by gp120-speci®c antibodies plays an important
role in virus clearing and depletion of gp120-coated CD4 cells.45 Another type of cell
that may play an important role in ®ghting HIV is the natural killer (NK) cell. These
cells are important in innate immunity to viruses and other intracellular pathogens, do
not require prior sensitization, and are not major histocompatibility locus antigen
(HLA) restricted. NK cells have been shown to suppress HIV-1 entry and replication
in vitro and are an important source of CC chemokines.46 Furthermore, low NK
number predicted a drop in CD4 cell numbers and rapid progression to AIDS.47 In
addition, poor NK cell response to IL-2 or IFN-a was prospectively associated with
faster progression to clinical AIDS and death.48 Interestingly, Ironson et al49 found that
natural killer cell cytotoxicity (NKCC) and NK number may be protecting the health
620 E. G. Balbin, G. H. Ironson and G. F. Solomon

of asymptomatic HIV-positive individuals with low CD4 numbers (550/mm3), as both

NKCC and NK number were relatively preserved in this special group.
Immune activation, as well as helper T cell depletion, is associated with disease
progression. Soluble immune activation markers such as b2-microglubulin and
neopterin have negative prognostic implications.50 Neopterin is released in large
quantities by human macrophages on stimulation with interferon-g (IFN-g). Another
soluble marker of immune activation that has recently been shown to predict disease
progression is TNF-RII.27 Cytokine imbalance has also been shown in progression of
HIV. As disease progresses, there is a shift from T helper-1 cytokines that stimulate
cellular immunity (IL-2, IFN-g) to T helper-2 cytokines that stimulate primarily
humoral immunity (IL-4, IL-10).51 Decreased production of IFN-g is associated with
disease production.52 Another cytokine, IL-16, dramatically inhibits p24 release into
culture supernatant, is high during asymptomatic periods, and drops on progression to
disease.53 Interleukin-12 (IL-12), a key factor in the initiation of cellular immunity, may
play an important role in HIV, both for its enhancing e€ects on natural killer cell
activity and for driving the di€erentiation of the T helper toward a Th1 response, as
opposed to the Th1±Th2 imbalance seen in AIDS patients.54 In addition, administration
of IL-15 has shown promise in expanding NK cell populations in HIV infected
individuals.55 Finally, HIV-1 Tat, an HIV regulatory protein essential for HIV-1
replication, plays a crucial role contributing to immune dysfunctions by inhibiting T
cell proliferation and phagocytosis, IL-12 secretions and NK-cell activity.56

Other factors
Route of transmission has been considered a possible reason for di€erential rate of
progression of HIV infection. Although some studies claim faster progression for
homosexual men19, presumably because of trans-mucous membrane route of trans-
mission, a comparison of injecting drug users and homosexual men with documented
dates of seroconversion utilizing 12 cohorts found no di€erences.57 The authors note,
however, that pre-AIDS mortality is higher in intravenous drug users. However,
continuing use of addictive drugs, particularly crack cocaine, is associated with faster
progression to AIDS.22 Finally, sexually transmitted diseases are cofactors for the
progression of HIV disease.7

PSYCHOSOCIAL PREDICTORS OF DISEASE PROGRESSION IN

HIV/AIDS

Several psychosocial factors have been explored as possible predictors of disease

progression in HIV infection. In this section we review the evidence for a number of
these variables including: stressors, depression and distress, coping, social support and
loss, disclosure and emotional expression, and adherence. It is important to remember
that, in addition to these psychosocial variables, behaviours such as practising safer sex,
not sharing needles, selecting an AIDS-knowledgeable physician, and adhering to
medical regimens are of key importance. It is hoped that the further elucidation of
psychosocial variables relating to slower progression may give guidance both to
individuals with HIV/AIDS and their health care providers.
 Psychoneuroimmunology of HIV/AIDS 621

Stressors, including life events

The strongest evidence for the role of life stress in HIV disease progression comes from
a longitudinal study of 93 initially asymptomatic HIV positive gay men followed for up
to 42 months and assessed every 6 months.58 Higher severe life stress increased the
odds of HIV progression fourfold in those followed for at least 2 years. Cole and
colleagues59 found that death of friends and lovers from AIDS predicted the develop-
ment of symptoms. Loss and its associated bereavement have also been related to
subsequent CD4 decline.60
Other immune markers relevant to HIV have also been negatively impacted
longitudinally by life stressors such as bereavement, including numbers of natural killer
cells and CD8 lymphocytes61, natural killer cytotoxicity (NKCC), and T cell prolifera-
tion to phytohaemaglutinin (PHA).62 The evidence for an impact of life stress on AIDS
progression is not uniformly found, however. Kessler et al63 found no relationship
between 24 stressor events and either CD4 declines or the development of symptoms.
Rabkin et al64 also found no relationship between stress and subsequent CD4 or CD8
change over 6 months but did ®nd a suggestive relationship between depression and
symptom development. While, overall, the evidence is mixed, the study ®nding the
most clear relationship58 measured life events most carefully. They utilized an
interview and a stress rating procedure that included training of raters and develop-
ment of a manual, rather than estimation of life events by questionnaire only. Finally,
sometimes a life stressor in combination with another variable may have a more
powerful impact than a life stressor alone. Such was the case when Kemeny et al65
found that bereavement was related to subsequent CD4 decline only when negative
expectancies were also present.

Depression and distress

In 1993 two major large longitudinal studies published simultaneously in JAMA found
opposite results for the predictive power of depression for HIV progression. The study
by Burack et al66 found depression was related to subsequent CD4 decline over
5.5 years in a cohort of 277 HIV-positive men. In contrast, Lyketsos et al67 found that
depression did not predict a faster CD4 decline in a sample of 1809 gay men followed
for 8 years. Neither study was able to demonstrate a relationship between depression
and mortality, although a subsequent longitudinal study of 402 HIV-positive gay men
followed for up to 7.5 years did ®nd an association with higher mortality.68 Patterson
et al69 also found that depression was related to shorter longevity controlling for
symptoms and CD4 cell change. Rabkin and colleagues64 also found a suggestive
relationship between depression and symptoms, although they found no relationship
between depression, distress, stress and CD4 or CD8 change over a 6-month period.
Vassend et al70 found negative a€ectivity (anxiety, distress, tension) was related to
subjective symptoms but not immune markers. Emotional distress predicted disease
progression in another cohort over 12 months.71
Finally, there has been some question about whether the impact of depression/
distress may be di€erent at di€erent levels of CD4 lymphocytes. One study72 found
that psychological distress predicted development of symptoms, but only in a group
with low initial CD4 number, while another study66 found a faster decline in CD4
counts for depression only in those with high CD4 counts.
Is there a particular characteristic of depression that may be related to disease
progression more strongly than others? Studies by Kemeny and colleagues73 suggest
622 E. G. Balbin, G. H. Ironson and G. F. Solomon

that chronic depression may be important. They found that when depression was
sustained (over a 2-year period) there was a faster decline in CD4 counts compared to
non-chronically depressed counterparts over a 5-year period. In other studies, Kemeny
et al65 tried to disentangle depression from bereavement and found that depression
was related to HIV progression only in the non-bereaved group. Thus, depression
during bereavement may represent a normal working through of loss. Finally, while
Perry and colleagues74 found no relationship between 22 psychosocial variables and
CD4 number, there was an association for hopelessness, an aspect of depression.
In summary, while the evidence is not entirely consistent, there does appear to be a
relationship between depression and disease progression. This relationship may be
strong in certain circumstances, such as more severe chronic depression, depression
unrelated to bereavement, and in those who are hopeless.

Coping
Several studies have investigated the relationship between styles of coping, such as
active confrontational coping versus denial or disengagement, and subsequent health in
HIV infection. For example, Ironson et al75 found that reacting to the news that one
was seropositive for HIV with denial and behavioural disengagement was associated
prospectively at 1-year follow-up with greater CD4 decline and lower T cell
proliferative response and with a greater likelihood of symptoms or death at 2-year
follow-up. Similarly, individuals with high levels of denial/repression were more likely
to develop symptoms of AIDS at 6-month and 12-month follow-up.72 Conversely,
three studies showed that active coping was related to better outcomes longitudinally
in HIV populations. In the ®rst, Blomkvist et al76 found that `active optimistic coping
behavior' was negatively related to mortality over 1±7 years in a haemophiliac cohort.
Mulder et al77 found that active confrontational coping was related to decreased clinical
progression at 1-year follow-up in a cohort of gay men. Finally, Vassend et al70 found
that HIV-positive individuals who had lower scores on measures of active problem-
related coping (positive re-appraisal, seeking social support) were more likely to
develop AIDS at subsequent follow-up. A clear interpretation that denial is bad and
active coping good is premature, however, as two other studies with what initially
might seem like discrepant ®ndings from the above studies require integration. In the
®rst, Reed et al78 showed that realistic acceptance was a signi®cant predictor of
decreased survival time. While this might seem discrepant with the denial ®ndings
above, a closer look at the items (`prepare myself for the worst') suggests that they
may be measuring a fatalism or pessimism dimension, thus ®tting in with the literature
reviewed in the next section. Mulder et al79 found that avoidance coping was associated
with a lower rate of CD4 decline over 7 years and fewer syncytium-inducing HIV
variants. Earlier presentations of these data referred to this construct as distraction.80
One way of integrating this ®nding is that it may be most e€ective to avoid obsessive
rumination with a healthy dose of distraction, while also avoiding the extremes of
denial or acceptance to the point where fatalism or behavioural disengagement occurs.

Cognitive mindset (negative expectancies, optimism, ®nding meaning)

Other studies have explored how a constellation of variables, which we refer to as
cognitive mindset (negative expectancies, optimism, and ®nding meaning), may a€ect
the course of HIV disease. As noted above, the study by Reed et al78 found that a
 Psychoneuroimmunology of HIV/AIDS 623

variable relating to fatalism was a signi®cant predictor of decreased survival time. In

another study, the same group found that negative expectancies in combination with
bereavement81 predicted faster time to AIDS-related symptoms in the next 2.5 to
3.5 years among initially asymptomatic HIV-positive gay men. Another way of looking
at this ®nding is that bereavement alone did not predict poorer health and that one's
outlook after the loss was what was important. Another cognitive mindset, negative
attributions (in particular, attributing negative events to aspects of the self),
signi®cantly predicted faster CD4 decline.82 Thus, three studies support the notion
that a negative mindset is related to faster progression. Conversely, a positive mindset
may be protective. Optimistic outlook, including anticipating future activities, was
related to lower mortality during follow-up in a group of haemophiliacs.76 Finally, an
intriguing study measuring ®nding meaning in response to an HIV related stressor
found that this construct was related to slower CD4 decline and lower mortality over
a 2- to 3-year follow-up.83 In summary, negative mindsets appear to be related to faster
progression, whereas positive mindsets appear to be protective of health.

Social support and loss

As noted above, loss and its associated bereavement have been related to the
development of symptoms59, subsequent CD4 decline60, and to poorer NKCC and
proliferative response to PHA.62 While bereavement alone may not always lead to
faster progression, in combination with negative expectancies it can be much more
deleterious.81
Social support, in general, presents a mixed picture. One study showed a positive
e€ect on health; two showed a positive e€ect but only for the sicker (low CD4 count
or with symptoms) individuals; one showed no predictive utility; and one showed
deleterious e€ects. Theorell et al84 found that high social support was associated with a
slower drop in CD4 count over subsequent years in a cohort of haemophiliacs.
Patterson et al69 found that large network sizes predicted longevity among those with
AIDS, but not among other subjects. Solano et al72 found that low social support was
related to the development of symptoms only in those with low CD4 numbers. In
contrast, Eich-HoÈchli et al85 found that social resources were not related to disease
progression after 2 years. Finally, Miller et al86 found that, contrary to expectation,
lower levels of loneliness predicted more rapid levels of CD4 declines, and loneliness
was not related to mortality or development of symptoms. In their review, Miller and
Cole87 note accelerated disease progression for gay men in the early stages of infection
with extensive networks of personal relationships. These studies suggest that social
support can often be helpful, particularly when one gets sicker, but social networks
can also be deleterious, especially for gay men during early stages of infection.
A more recent study evaluated the e€ects of three psychosocial variables ± stress,
depressive symptoms and social support ± in a prospective 5-year design with
repeated (6 month) assessments.88 Faster progression to AIDS was associated with
more cumulative stressful life events, more cumulative depressive symptoms and less
cumulative social support. When all three variables were analysed together, stress and
social support remained signi®cant in the model. At 5.5 years, the probability of
getting AIDS was two to three times as high among those above the median for stress
or below the median for social support. Even two moderate stressors increased AIDS
risk twofold compared with no stressors. This study is important for utilizing
cumulative measures and a clinical outcome, AIDS, rather than `surrogate' markers of
progression.
624 E. G. Balbin, G. H. Ironson and G. F. Solomon

Only one psychosocial variable, social support, has been tested in the primate model
of AIDS, simian immunode®ciency virus (SIV) infection. Housing relocations and social
separations in the 90-day period before SIV inoculation and in the 30-day period after
inoculation were associated with decreased survival.89 Even a subset of those not
socially separated but housed with new cage mates after SIV inoculation had decreased
survival. Social stress thus has similar negative health consequences in our retrovirally-
infected primate cousins, rhesus monkeys.

Other variables
The role of a number of other psychosocial variables, including disclosure, adherence
and hardiness, has been examined longitudinally. Cole et al90,91 have investigated the
role of disclosure and found that gay men who concealed their sexual orientation had a
faster course of HIV infection by 1.5 to 2 years. In subsequent research, however, they
found that a subset of gay men who were rejection-sensitive did better if they kept
their homosexual orientation concealed.91 Perhaps related, we showed that long-term
survivors of AIDS had higher emotional expression than an HIV-positive comparison
group. Ironson and colleagues found a constellation of activities related to involvement
in a stress management intervention for HIV ± including the practice of relaxation
techniques, doing homework, and attending sessions ± as signi®cantly related to
disease progression to AIDS at a 2-year follow-up period.75 More research is needed to
determine why health outcomes improved. For example, health could be a direct
e€ect of the intervention on stress responses and coping, or it could be a factor
unrelated to the intervention such as conscientiousness, which may in¯uence attend-
ance and doing homework as well as taking medication and getting a competent
doctor. Lastly, Solomon et al92 demonstrated that emotionally hardy individuals, those
with a sense of commitment and control and an ability to see adversity as a challenge,
were more likely to be alive as follow-up than less hardy individuals.

PSYCHOLOGY OF HEALTH AND LONG SURVIVAL WITH HIV/AIDS

Our current research concerns an intensive investigation of two unique groups of

HIV-positive individuals. The ®rst are long-term survivors (LTS) of AIDS. These
individuals have survived twice as long as expected after having an opportunistic
infection or neoplasm. In 1996 when the study started, the length of time to de®ne
long-term survivor status was 4 years. (With the widespread availability of protease
inhibitors this time has increased, but our subjects had to meet the 4-year criterion
before starting on protease inhibitors.) The second group is a `rare' group of HIV-
positive people with very low CD4 counts (550/mm3) who have had a period of at
least 9 months with no AIDS-related symptoms. This group is quite rare because most
people with CD4 counts less than 50 are seriously symptomatic.93 As was true for the
LTS group, individuals in this `healthy low CD4' group (HLC) had to meet the
inclusion criteria before starting on protease inhibitors. A third group of HIV-positive
individuals has been utilized as a comparison (COMP) group. This comparison group
initially had between 150 and 400/mm3 CD4 counts; they are being followed
longitudinally for 3 years. Most of this group will not become long-term survivors, and
most will have symptoms when their CD4 cells fall below 50. Over the past 2 years,
we have begun reporting results contrasting the LTS (n ˆ 60) versus COMP (n ˆ 120)
groups, and the HLC (n ˆ 60) versus COMP (n ˆ 120) groups, on major psychological
 Psychoneuroimmunology of HIV/AIDS 625

variables. The psychological variables examined in the comparisons involve four

factors, which we hypothesized94 might be related to long survival: health care,
connectedness, maintaining perspective, and life involvement. So far, we have found
some evidence for each of the factors. Long-term survivors were signi®cantly higher
than the comparison group on collaborative relationship with doctor, being partnered,
having high life involvement, and emotional expression, and were signi®cantly lower
on hopelessness.133 The healthy low CD4 group, interestingly, had relatively preserved
natural killer cell cytotoxicity (NKCC) and NK number49, suggesting that NKCC may
be a factor protecting the health of these people and compensating in some way for
the loss in CD4 (helper T) cells. Since NKCC is one of the immune variables for which
there is strong evidence of a stress-immune connection95, we looked for psychological
variables in particular that might explain this relative preservation. The HLC group
had both lower perceived stress and lower depression96 than the COMP group. Finally,
the two unusual groups (LTS and HLC) were combined and compared across three
subscales (compliance, de®ance, collaboration) assessing their relationships with
treating physicians. The `unusual' groups were signi®cantly higher on the collaborative
relationship with doctor scales. Comparisons on other psychological characteristics
revealed that the LTS ‡ HLC group scored signi®cantly higher on life involvement and
on a composite of adaptive minus maladaptive coping scales. Both our study and other
studies on long survivorship94 lend support to the four factors noted above (health
care, connectedness, maintaining perspective, and life involvement) and to the notion
that psychosocial factors make important contributions to the maintenance of health
and long survival with HIV/AIDS.

PSYCHONEUROIMMUNE PATHWAYS IN HIV

In a previous section we reviewed studies illustrating a prospective relationship

between psychosocial factors and disease progression in HIV/AIDS. This section
considers the immune pathways by which stress, distress, and poor coping might
contribute to progression of HIV infection. There is ample literature showing that
there is an impact of stressors on the immune system in healthy people.95,97 These
include: loss and the associated bereavement, divorce, the stress of being in a poor-
quality marriage, the stress of caregiving, lack of social support/loneliness, and
trauma.98 Reactions to stress, such as depression, poor coping and alcoholism, have also
been related to poorer immune function. For example, decreased T cell function as
measured by responsivity to mitogens has been found in bereavement99, poor marital
quality100, and anxiety.101 Depression is associated not only with poorer T cell
function, especially in older individuals, but also with immune activation.102,103 (As
mentioned, immune activation is a negative prognostic factor in HIV infection.)
Decreased NK cell activity has been found in bereavement104, during stressful
commonplace events105, in individuals who are lonely106, in major depressive disorder
and alcoholism107,108 in response to trauma, and from lack of sleep.109 Poorer control of
Epstein±Barr virus (EBV), a latent virus that is the causative agent for mononucleosis
and Burkitt's lymphoma, has also been related to academic stress in medical
students110, academic stress in West Point cadets111, and emotional repression.112
Other latent viruses, such as herpes simplex type 2 (HSV-2), the causative agent for
genital herpes, and HSV-1, the cause of cold sores, are also reactivated by stress.113±115
(Activation of latent herpes group viruses, including EBV, is the result of suppression of
cellular immunity.) Cytokine production has also been a€ected by stress, including the
626 E. G. Balbin, G. H. Ironson and G. F. Solomon

Th1 cytokines interferon-gamma and IL-2.105,116,117 Finally, poorer antibody response to

vaccination has been associated with stress for both the ¯u vaccine118 and the hepatitis
vaccine.119

PNI studies in HIV populations

The immune measures most a€ected by stress95 that are particularly relevant to HIV
infection include but are not limited to: helper and cytotoxic T cells, T cell activity,
NK cell activity, and herpes virus antibody titres. As noted in the previous section on
psychosocial predictors of disease progression, both stressors and distress have been
related prospectively to CD4 decline. These predictors include stressful life events58,
depression66, and bereavement in combination with negative expectancies.81 A variety
of coping strategies including denial75, and negative attributions82 have been related to
a steeper CD4 cell decline, while other coping strategies such as distraction79 and
®nding meaning83 have been related to a slower CD4 decline. Finally, better social
support84,86 and disclosure of HIV status90 have also been related to slower CD4
decline. While most stress management intervention studies have found no impact on
CD4 numbers (see Ironson et al98 for a review) a bereavement support group
intervention was associated with bene®cial e€ects on the CD4 counts in gay men who
had su€ered a recent loss.120 There are only a few studies relating psychological
variables directly to other immune measures in HIV populations. T cell responsiveness,
as measured by proliferative response to PHA, was measured prospectively in an HIV
population by Ironson et al.75 Lower T cell proliferation to PHA was predicted by an
increase in denial surrounding noti®cation of HIV serostatus, and both lower
proliferation to PHA and denial increase predicted subsequent faster disease
progression. NK cell cytotoxicity has also been shown to be stress-responsive in an
HIV population; individuals receiving noti®cation of HIV seropositivity had a signi®cant
drop in NKCC.121 Furthermore, a stress management intervention utilizing massage
produced a signi®cant increase in NKCC, as well as a signi®cant increase in cytotoxic
CD8 cells and soluble CD8 receptors.122 Leserman et al61 found that stress and
depression found jointly was associated longitudinally with decreased NK cell numbers
and decreased CD8 lymphocytes, providing more evidence of a stress±immune link in
an HIV-positive population. Finally, several studies have been done relevant to latent
viruses in HIV. In a cross-sectional study of HIV-infected individuals, Robertson et al123
found that distress was related to higher antibody titres (and, thus, poorer control of
the latent virus) for HSV but not for EBV or CMV. A stress management intervention
with HIV-positive gay men had a favourable impact on EBV titres40 and on HSV-2 and
HHV-6 titres.125 Thus, there are a number of immune measures for which there is a
psychoimmune link in HIV populations, but more needs to be done to discern
transduction of psychological in¯uence into HIV-relevant immunological processes. As
of yet, there is not adequate research in persons with HIV linking psychological stress
to include viral load, cytokine production, and CD8 number and cytotoxicity.

Immune system to brain communication; HIV dementia

Immune system to brain communication is the second `limb' of psychoneuroimmuno-
logy, under which may be subsumed immunological processes occurring within
the brain (neuroimmunology). The brain contains immunologically-competent cells,
microglia, which are ®xed macrophages. HIV can infect macrophages, which, like
helper T lymphocytes, possess the CD4 receptor. Some strains of HIV are
 Psychoneuroimmunology of HIV/AIDS 627

macrophage-trophic rather than lymphotropic. Thus, HIV infection of the brain and
complex immunological processes within the brain are responsible for the develop-
ment of AIDS-related dementia, in some, but by no means all, patients with AIDS.
Moreover, some AIDS-related symptoms are the result of the action of products of
immune activation on the brain. Pro-in¯ammatory cytokines such as IL-1, IFN-g, and
TNF-a, can produce fatigue, cognitive impairment and hypersensitivity to pain
(hyperalgesia).126 However, these important psychoneuroimmunological topics are
beyond the scope of this chapter.

Endocrine linkages
Distress-related endocrine changes may also contribute to HIV progression either
directly or through impacting the immune system. NK cell activity is synergistically
inhibited by cortisol and HIV envelope peptide.127 Corticosteroids impair several
aspects of cellular immunity, including NK cell activity, responsiveness to mitogens,
cytokine production and T cell populations.128 Another stress hormone, norepi-
nephrine, accelerates HIV replication via suppression of cytokine production.129
Recently, there has been interest in the possible role of dehydroepiandrosterone
(DHEA) in HIV.130 DHEA has been shown to have inhibitory e€ects on HIV replication
in vitro, and serum levels of DHEA may be an independent predictor of HIV
progression. It is interesting to note that stress management interventions have been
shown to have a signi®cant impact in reducing cortisol120,122 and bu€ering a decrease in
the DHEA/cortisol ratio seen in a non-intervention HIV-positive control group.131

SUMMARY AND CONCLUSION

A considerable body of evidence suggests that psychosocial factors play an important

role in progression of HIV infection, its morbidity and mortality. Thus, psychosocially-
in¯uenced neuroendocrine-immune relationships are relevant to HIV/AIDS.
Among the most potent psychological in¯uences relating to faster disease progres-
sion are life-event stress such as bereavement, sustained depression, denial/avoidance,
coping, concealment of gay identity (unless one is rejection-sensitive) and negative
expectancies. Conversely, protective psychosocial factors include active coping, ®nding
new meaning, and stress management. Social support had con¯icting ®ndings; it may
be especially helpful in the later stages of the disease but deleterious for gay men in
the early stages. Adding evidence about protective factors are studies investigating
`experiments of nature', that is, long survivors or people who have low CD4 counts
but remain healthy. Studies from these extraordinary people lend support to four
hypothesized factors: following healthy self care, maintaining connectedness, having a
sense of purpose in life, and maintaining perspective. More speci®cally, we found
evidence for protective e€ects on health of life involvement, collaborative relationship
with doctor, emotional expression, depression (conversely), and perceived stress
(conversely). It is thought that these factors might work through negating behavioural
disengagement and reducing distress.
What biological/immunological factors may transduce psychosocial factors into
relative health or into illness progression? The ®eld of psychoneuroimmunology
provides much evidence for the hypothesized mechanisms (reviewed in the PNI
pathways section). Examples of naturalistic stressors a€ecting the immune system are
numerous. A€ective states, such as depression, suppress cellular immunity, both
628 E. G. Balbin, G. H. Ironson and G. F. Solomon

speci®c (CD8) and non-speci®c (NK), as well as leading to immune activation, which
would be expected to have a negative impact on HIV progression. Perhaps the most
`psychosocially sensitive' of immune components, the natural killer cell, may be of
particular relevance and deserves further attention. Our group49 found that NK cell
number and cytotoxicity is relatively preserved in healthy HIV-infected people with
very low CD4 counts, and may, therefore, be protecting the health of this group.
Herpes virus antibody titres are also a€ected by psychosocial stress, and latent virus
activation is of direct relevance to HIV. Psychosocial in¯uences on cytokine pro-
duction, in view of the shift in Th1 to Th2 cytokines as disease progresses, also deserve
further attention. Stress responsive hormones, such as cortisol and norepinephrine,
also provide a mechanism for the deleterious e€ects of stress on HIV. For example,
norepinephrine, when combined with gp120, may have especially harmful e€ects on
immune cells. Of course, biological factors are also major determinants of disease
progression and include: genetics and age of the host, viral strain and virulence, and
several immune response factors on which psychosocial in¯uences could impact.
The human species (Homo sapiens) has existed through numerous plagues and wars,
roughly 200 000 years.132 During this time the immune system has presumably played a
crucial role in our ability to ®ght o€ bacteria, viruses, toxins and parasites, and has
thereby helped bring about the survival of our species. Although our ability to stay
healthy has been impacted by major advances in the 20th century, such as antibiotics,
sanitation, diagnostic capabilities, vaccines and nutrition, we are still faced with the
advent of drug-resistant strains of microorganisms, and many viruses for which there
are no vaccines. Thus, even with our modern medical advances, we still rely on the
diversity and complexity of our immune system for protection. Immunological
research in the era of HIV/AIDS has taught us much about our immune system that we
may not have otherwise known. Even though the immune system is quite complex, we
have provided evidence that it is also very sensitive to, and readily in¯uenced by,
psychosocial factors. The potential for such psychoneuroimmunological interactions in
HIV infection is enormous. Thus, psychosocial factors do appear to in¯uence the
outcome of disease.
The authors hope that the evidence summarized in this chapter has convinced the
reader of the relevance of psychoneuroimmunology to an understanding of the clinical
course of HIV infection and has led the reader to a better understanding of the
psychobiological pathways by which this might occur. It is likely that sensitivity to
psychosocial in¯uences on health and longevity with HIV/AIDS will remain important
even in the new era of highly active anti-retroviral treatment.

Acknowledgement
We wish to thank the National Institute of Health for funding the research reported in the
section on Psychology of Health and Long Survival with HIV/AIDS (RO1MH53791).

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