Progress

in

Pediatric
Cardiology
ELSEVIER Progress in Pediatric Cardiology 7 (1997) 19-31

Pathogenesis of HIV infection in children

Grace M. Aldrovandi*
Universi@ ofAlabama at Birmingham 256 Bevill Biomedical Research Building 845 19th Street South,
Birmingham, AL 35294-2170, UK

Abstract

The increasing numbers of children infected with human immunodeficiency virus (HIV), the etiologic agent of the Acquired
Immunodeficiency Syndrome (AIDS), affects widely diverse socially and geographical populations. This review is intended to
highlight key aspects of HIV pathogenesis especially as it relates to children. Topics include aspects of the virus itself, the cells
it infects, the in vivo dynamics of infection and the host immune response to the virus. Discussion of the problems of diagnosis
and management of children with HIV-l infection will also be briefly considered. 0 1997 Elsevier Science Ireland Ltd.

Keywords: Human immunodeficiency virus; Acquired immunodeficiency syndrome; Pediatrics; Pathogenesis; Natural history

1. Introduction are only 40-50% identical at the nucleotide level

In recent years, there has been an evolving under-
standing of AIDS as a dynamic viral infection. An
appreciation of the complex nature of this infection is
essential to comprehending the challenges involved in
the treatment of HIV-l infected persons. This review
will focus on our current understanding of the dy-
namic nature of the mechanisms involved in the es-
tablishment and progression of this disease. Consider-
ation will also be given to the unique problems in-
volved in the diagnosis and management of children
infected with HIV.
There are two related but distinct subtypes of HIV:
types 1 and 2. Both of these viruses are associated
with AIDS, however, there is some recent evidence
that HIV-2 is less pathogenic [l] and less likely to be
transmitted [2-81. Although sporadic cases have been
reported in the US [9] and elsewhere, HIV-2 is cur-
rently only endemic in West Africa. HIV-l and HIV-2
*Tel.: + 44 205 9342456; fax: +44
gracea@uab.edu
however, some serological reagents cross react
[lo-141. This paper will focus on HIV-l infection
since it is by far the more prevalent and more
thoroughly characterized.
2. Structure and life cycle of HIV
HIV is a member of the retrovirus family. Retro-
viruses are a distinct subset of RNA viruses in which
the viral RNA genome is transcribed to DNA by an
RNA dependent DNA polymerase (reverse transcrip-
tase) in the host cell. This DNA is then integrated
into the infected cell’s chromosomal DNA as a
provirus, and subsequently behaves like a cellular
gene. Thus, under appropriate conditions the proviral
genes are expressed and the progeny virus made.
Structurally HIV has a cylindrical eccentric core or
nucleoid containing the diploid RNA surrounded by
reverse transcriptase and nucleocapsid (NC) proteins
(~9, p6) (see Fig. 1). These nucleoid components are
205 9341640; email: enclosed by the capsid antigen p24 forming the nucle-
ocapsid. The matrix antigen p17 surrounds the nucleo-

1058-9813/97/$17.00 0 1997 Elsevier Science Ireland Ltd. All rights reserved.

PZZSlOSS-9813(97)00198-7
20 GM Aldrovandi /Progress
capsid and lines the inner surface of the envelope of
the virus. The surface of the virion contains 72 knobs
of the envelope glycoprotein gp120. The gp120 is
non-covalently anchored to the viral envelope by the
transmembrane protein gp41. This weak interaction
allows the gp120 to be easily stripped off the virion
and may in part account for the relatively poor infec-
tivity of this virus. The viral envelope is a lipid bilayer,
derived from the host cell plasma membrane and
consequently contains various host cell antigens.
HIV can infect T-lymphocytes, monocytes/macro-
phages, dendritic cells and microglia in the central
nervous system. Infection begins with binding of the
gp120 on the viral envelope to a cellular receptor.
The CD4 molecule is the principle receptor, however,
there is some evidence that HIV can enter cells via
the complement receptor, Fc or the Gal/C receptor
[15,16]. This attachment is believed to result in con-
formational changes exposing the gp41 transmem-
brane component permitting virus-cell membrane fu-
sion and subsequent internalization of the virion. Re-
cently, it has been demonstrated that’members of the
Legend
1 ss RNA
IQ p66RTiRNAase H
l P6
a Int egrase
Fig. 1. Schematic representation
in Pediatric Cardiology 7 (1997) 19-31
chemokine receptor family serve as co-receptors for
HIV-l infection [17-221.. Chemokines are proteins
involved in inflammatory responses and have been
found in vitro to suppress HIV replication 1231. Some
individuals who have been able to escape infection
despite extremely high risk multiple exposures to HIV
have defects in these receptors 124-261.
After entry into the cell, HIV-l undergoes reverse
transcription and then integration into the host
genome. Initiation of RNA transcription of the provi-
ral DNA is due to cellular factors and appears to
depend on the overall state of activation of the cell.
Gene expression is regulated by various virus-specific
proteins and can be influenced by cytokines and co-
infection with other viruses. Translation of singly and
multiply spliced mRNAs results in the production of
structural, replicative, regulatory and other proteins,
which co-assemble at the inner surface of the cell
membrane. The proteins insert themselves into the
cell membrane where the virion is assembled and
then released.
The viremia in HIV-l infection is sustained by
Host proteins
gP 120
gP 41
P24
of the morphologic structure of HIV-l.
 G.M. Akirovandi /Progress
rapid, high level viral replication, requiring continu-
ous reinfection and destruction of CD4+ T cells.
Recent elegant mathematical modeling studies have
provided insight into the kinetics of viral replication
which are summarized in Fig. 2. Analysis of adults
with moderate to advanced disease have revealed a
very dynamic process of viral production and clear-
ance [27-291. On average greater than 10n virions
per day are released into the extracellular space; the
half-life of these vii-ions is only approximately 6 h [29].
The average life span of a productively infected cell is
about 2 days [27,28]. The time from release of a virion
from one cell until it infects another cell and results
in the release of a new generation of k-ions is re-
ferred to as the generation time. For HIV the genera-
tion time is approximately 2.6 days [29]. It is estimated
that about 5% of the total body CD4* cell population
are being destroyed daily [27,28]. Thus the immune
system must constantly be replenishing its losses. In-
terestingly, the rates of T cell recovery in persons
treated with potent anti-retrovirals, tend to be higher
ELLS INFECTED
WITH DEFECTIVE VIRUS
ONG -LIVED POPULATIONS
< 1% OF VIRUS PRODUCTION
PRODUCTIVELY INFECTED
LYMPHOCYTES
AVERAGE t ,,2 1.6 days
Fig. 2. Schematic representation of the dynamics of HIV-l
in Pediatric Cardiology 7 (1997) 19-31 21
in persons with lower baseline CD4+. This suggests
that the decline in CD4+ cell number that precedes
the ultimate immune system collapse may largely re-
flect increased HIV replication and not immune ex-
haustion [28].
Clearance rates do not appear to vary substantially
between persons with different CD4+ counts or viral
load, suggesting that viral clearance may not be de-
pendent on specific host immune responses. Thus, the
extent of the viremia depends on virus production.
The factor(s) that mediate this clearance (e.g. inher-
ent instability of virions, the reticuloendothelial sys-
tem, etc.) are as yet unidentified. Thus, HIV infection
involves a dynamic, continuous process of de-novo
infection of target cells that produce the virus for a
very short time before being consumed in the process
of viral replication. Studies of viral and cellular dy-
namics in children have yet to be performed. There
are several important differences between young chil-
dren and adults which may have a profound effect on
viral and cellular dynamics. Among these are: much
LYMPHOCYTES
ACTIVATED
UNINFECTED
LYMPHOCYTES
infection in vivo.
22 GM Aldrovandi /Progress in Pediatric Cardiology 7 (1997) 19-31

Table 1
Conditions associated with categories of disease

Category A Category B Category C

Have two or more of the
conditions listed below but
no categories B and C
conditions
Lymphadenopathy (> 0.5 cm
at more than two sites)
Hepatomegaly
Splenomegaly
Dermatitis
Parotitis
Recurrent or persistent
upper respiratory infection,
sinusitis, or otitis media
Examples of conditions in clinical Multiple or recurrent serious bacterial infections
category B (septicemia, pneumonia, meningitis, bone or joint
infection, or abscess of an internal organ)
Anemia ( < 8 g/dl), neutropenia Candidiasis, esophageal or pulmonary
( < 1000/mm3), or thrombocytopenia Coccidiomycosis, disseminated
( < 1000 O00/mm3) persisting > 30 days Cryptococcosis, extrapuhnonary
Bacterial meningitis, pneumonia or Cryptosporidiosis or isosporiasis with diarrhea
sepsis (single episode) persisting for > 1 month
Candidiasis, oropharyngeal (thrush), Cytomegalovirus disease with onset of symptoms prior
persistent (> 2 month) in a child > 6 month to 1 month of age
Cardiomyopathy Cytomegalovirus retinitis (with loss of vision)
Cytomegalovirus infection, with onset Encephalopathy in the absence of a concurrent illness
> 1 month of age other than HIV infection that could explain the findings
Diarrhea, recurrent or chronic, HSV infection causing a mucocutaneous ulcer
Hepatitis, persisting for > 1 month; or as the etiology of
HSV stomatitis, recurrent( > 2 episodes bronchitis, pneumonitis or esophagitis
within 1 year) Histoplasmosis, disseminated
HSV bronchitis, pneumonitis, or Kaposi’s sarcoma
esophagitis within < 1 month of age Primary CNS lymphoma
Herpes Zoster involving > 2 distinct Lymphoma, Burkitt’s, large cell, or immunoblastic
episodes or > 1 dermatome M. Tuberculosis, disseminated or extrapulmonary
Leiomyosarcoma Mycobacterium infections other than tuberculosis,
LIP or pulmonary Iymphoid disseminated
hyperplasia PCP
Nephropathy Progressive multifocal leukoencephalopathy
Nocardiosis Toxoplasmosis of the brain with onset at > 1 month of age
Persistent fever (lasting > 1 month) Wasting syndrome in the absence of a concurrent
Toxoplasmosis, onset < 1 month of age illness other than HIV infection
Varicella, disseminated

higher CD4+ cell counts (see Table 11, infection
during the immunological development, an immature
immune system, and greater immune activation.
3. Genetic variation
The genetic homogeneity of initial infection with
HIV-l rapidly gives way to tremendous diversity
[30-321. As a result of this rapid genetic drift, HIV
infection in an individual is not due to a homoge-
neous virus but a population of viruses - a quasi-
species or a distribution of mutants within which each
daughter virion differs from that of its parent. Diver-
sity is present not only between individuals but within
an individual at any given timepoint. Moreover, this
heterogeneity is manifested at the molecular, biologic
and serologic levels. These quasispecies differ not
only in their genetic structure but their replication
kinetics, level of virus production, cytopathicity, cellu-
lar tropism and their sensitivity to immune responses
(see reference [33] for an excellent discussion); in no
small measure this accounts for HIV-l’s remarkable
adaptability. This diversity has in large part been
attributed to the intrinsic infidelity of reverse tran-
scription. It has been estimated that every possible
single point mutation would occur between lo4 and
10’ times per day in an infected person 1331. High
replication rate also means that even subtle selection
pressures will have dramatic effects on the population
of viruses. This also explains the virtually inevitable
and rapid emergence (within a few weeks) of drug
resistance. It also accounts for the ability of this virus
to escape what appears to be a very strong immune
response and eventually leads to the death of the
infected individual. Why certain individuals are able
to avoid and perhaps even escape this fate is an area
of considerable interest (see references [34-371).
4. Transmission of HIV
HIV is not an easily transmitted virus; direct con-
tact with infected bodily fluids is necessary. The risk
of transmission after percutaneous injury is much less
with HIV than Hepatitis B (0.2-0.5% vs. 2-40%)
[38,39]. The administration of zidovudine shortly after
exposure to HIV can decrease this risk by almost 80%
[38]. Most children acquire HIV perinatally, but even
by this route, only about 12-30% of children born of
HIV-infected women are themselves infected [40-431.
By administering zidovudine to the pregnant woman
this transmission rate can be decreased by two thirds
[44]. This ability to decrease transmission makes the
case for prenatal testing even more compelling [45,46].
There is evidence that transmission can occur in utero
 GM Aldrovandi /Progress
[47-491, intrapartum 1491 and post-partum via breast
feeding [50-521. The risk of transmission via breast
milk appears to increase if the woman acquires the
infection while lactating (approximately 26%), rather
than if she is infected prior to pregnancy (8-18%)
[50]. In most of the developed nations HIV positive
women are counseled to avoid breast feeding how-
ever, in less developed countries where malnutrition
and other infectious diseases are a major cause of
infant mortality the risks of HIV transmission are
outweighed by its benefits.
The proportion of transmission events that occur at
these different times is still uncertain, A working
definition of the timing of infection has been pro-
posed in non-breastfeeding population [53]. In utero
infection is believed to have occurred if HIV is cul-
tured from peripheral blood or detected by PCR
within 48 h of birth. Infants are regarded as being
infected intrapartum if peripheral blood samples ob-
tained in the first week of life are negative for HIV
culture, DNA PCR or both, and subsequently posi-
tive. Using this definition it is estimated more than
50% of children are infected intrapartum [47,48,54,55].
Preliminary studies suggest that the timing of infec-
tion has an influence on clinical course (see below).
HIV has been detected in amniotic fluid and in
fetal tissues as early as 8 weeks gestation [56-591. It
has also been detected in the placental trophoblast
particularly in Hoefbauer cells which are of
macrophage lineage [60]; all these cells can be readily
infected with HIV in vitro 161-631. Nevertheless, the
presence of HIV in the placenta is not directly related
to the risk of transmission to the infant [64,65]. There
is evidence that placental inflammation or damage
increases the risk of transmission [60,66,67]. The
mechanisms by which an HIV infected placenta serves
as an effective barrier against the virus are unknown.
During birth, the infants’ mucosal surfaces and
potentially traumatized skin are exposed to HIV in-
fected blood and cervical secretions. Evidence for
intrapartum transmission comes from studies of twins
born to HIV-infected women. The first born twin has
greater than a twofold higher risk (35% vs. 15%) of
contracting the virus [68]. Presumably the presenting
twin has a longer exposure to infected blood and
cervical secretions or has an increased incidence of
trauma during labor and delivery. However, this in-
creased risk was observed even in a comparison of
twins delivered by cesarean section (16% vs. 8%) [68].
Several other reports have agreed that cesarean sec-
tion can reduce the frequency of transmission [69-741,
further supporting the importance of events close to
delivery. Elective cesarean section is not routinely
advocated since it is estimated that 16 infants would
have to be delivered by cesarean section in order to
prevent one child from being infected [73]. Other
in Pediatric Cardiology 7 (1997) 19-31 23
interventions such as virucidal vaginal lavage during
labor, active and/or passive immunization are also
being studied.
5. Factors associated with perinatal transmission
There have been numerous attempts to discern
factor(s) which increase the risk of vertical HIV tran-
smission. Maternal, obstetrical, virologic and fetal fac-
tors have all been proposed as variables in determin-
ing perinatal transmission (see references [75-781 for
an excellent reviews). Discordant twins and the obser-
vation that women could have one infected child and
then subsequently deliver an uninfected child support
a multifactorial mechanism. Several studies have sug-
gested an association with maternal factors and an
increased rate of HIV transmission from mother to
child. Among these factors are: high virus load [79,80];
low CD4+ cell count [42,81]; and advanced clinical
disease state [66,67]. Other factors such as p24 anti-
genemia [42,82-841 viral phenotype 1841 and de-
creased maternal neutralizing antibody to autologous
virus are controversial [85-901. As discussed above,
placental breaches and/or events occurring at the
time of delivery such as infant exposure to maternal
blood, prolonged duration of ruptured membranes
(> 4 hours) and increased quantity of HIV in mater-
nal blood at delivery have also been associated with
an elevated risk of transmission. There is also some
evidence that HLA type may influence the susceptibil-
ity of an individual to infection [91,92]. Nevertheless,
none of these factors alone or in combination can
reliably predict the outcome in an individual case.
6. Diagnosis of HIV infection
In children older than 18 months and in adults the
diagnosis of HIV infection is made by detecting anti-
bodies to HIV. In adults, antibodies are usually de-
tected within 6-12 weeks post-infection. The period
between infection with the virus and the detection of
antibodies is known as the ‘window period’. Although
there are a few case reports of persons infected with
HIV not having antibodies against the virus these
cases are exceedingly rare [931. The determination of
HIV infection in children younger than 18 months is
complicated by the presence of maternal antibody.
The transplacentally acquired maternal IgG against
HIV is indistinguishable from antibody produced by
the infant. Thus, virtually all infants born to HIV-in-
fected women will have detectable antibodies to HIV.
These antibodies are usually lost by 7-9 months of
age but can persist for as long as 18 months of age
[42]. Therefore, the alternative methods discussed
below have been employed for the diagnosis of HIV
infection in young children. Only three methods, i.e.
24 G.M. Aldrovandi /Progress
virus culture, polymerase chain reaction (PCR) and
detection of p24 antigen are accepted by the Centers
for Disease Control and Prevention (CDC) for the
diagnosis of HIV infection in children younger than
18 months [94].
7. Serologic tests for HIV diagnosis
The standard test for screening for HIV infection is
the ELISA (enzyme-linked immunosorbent assay).
This tests uses antigens derived from disrupted extra-
cellular virions that are purified and immobilized on
beads or wells. Test serum is incubated with these
antigens and then treated to detect a spectrophoto-
metric color change. This test is only considered posi-
tive if it is positive on two or more repetitions. Most
of the kits will detect both HIV-l and HIV-2. There
was a recent report that an unusual serotype found in
Cameroon, Africa was not detected by some manufac-
turers’ kits in the US, however, in conjunction with
the CDC this problem has been rectified [95].
Once an ELISA is repeatedly positive, a confirma-
tory test such as a Western blot must be performed to
validate the results. The Western blot assay also uses
HIV antigen derived from purified, disrupted whole
virus. In this assay antigens are electrophoretically
separated into bands, transferred onto test strips of
nitrocellulose paper and then incubated with patient’s
serum. There are several different criteria for what
constitutes a positive Western blot. The CDC has
recommended that this assay be considered positive
on the identification of two of the following HIV gene
products ~24, gp41 or gp120/160 [13,96]. If fewer
bands are present the test is considered indetermi-
nate; if no bands are present the test is interpreted as
negative. Individuals with an indeterminate Western
blot should be referred to specialists for careful clini-
cal follow-up, repeat testing or testing by alternative
methods. Most laboratories in the US will only issue a
final report of HIV seropositivity if both the ELISA
and Western blot are positive. This combination of
currently licensed tests have a sensitivity and specific-
ity exceeding 99% [13,96]. These tests can rarely be
falsely negative especially if the person is hypogam-
maglobulinemic.
Since IgM and IgA antibodies do not cross the
placenta, their presence could be used to diagnose
infection of infants. Unfortunately, the sensitivity and
specificity of these tests, particularly in the first 6
months of life have been disappointing. Detection of
HIV-specific IgM has been neither sensitive or speci-
fic presumably because of low levels, transient pro-
duction and/or non-specific reactions. HIV-IgA can
be detected in sera, salvia and urine, however, prior
to 6 months of age it is neither sensitive or specific
in Pediatric Cardiology 7 (1997) 19-31
and after this timepoint, it is of moderate sensitivity
but high specificity [97-1001.
Other tests which have been used are HIV p24
antigen (Ag) and in vitro antibody production assays.
Detection of p24 Ag provides definitive proof of infec-
tion. The sensitivity of this test can be enhanced by
immune complex dissociation (ICD) of Ag-Ab com-
plexes in the sera. This easy and relatively inexpensive
test is only moderately sensitive; after 6 months of
age the sensitivity is approximately 80-100%
[101-1041. Since it does not rely on antibodies it is
useful for diagnosis of infants who are hypogamma-
globulinemic. Detection of HIV-specific antibody pro-
ducing B-lymphocytes has been used for diagnosis of
HIV infection; however, false positives and negatives
remain important limitations [105-1081.
8. HIV culture and PCR
The ‘gold standard’ for the diagnosis of HIV infec-
tion in infants is viral culture. Unfortunately, the
requirement for special laboratory facilities and highly
trained personnel limit its use outside of research
settings. In addition, this technique takes 2-4 weeks
to obtain results and is very expensive. The sensitivity
of polymerase chain reaction (PCR) is comparable to
viral culture and has the advantage of being extremely
rapid (l-2 days) [49,54,109-1121. The development of
commercial kits and methods to decrease the likeli-
hood of contamination have made PCR amenable for
use in the clinical laboratory [113]. Both viral culture
and DNA-PCR are of comparable but limited sensi-
tivity in identifying HIV infected neonates at the time
of birth or shortly thereafter [103,110,114]. Under 1
week of age only 20-30% of infected infants can be
identified by these techniques, however, at 4 weeks of
age this increases to approximately 90%. There is
excellent correlation between PCR and culture results
in the first 7 days of life, suggesting that the limiting
factor may be viral load. This would support the
prevailing hypothesis that in utero infected infants
would have more detectable virus early on compared
to those infants infected intrapartum.
9. Natural history of HIV infection
Infection of adults with HIV is classically followed
by three distinct virologic stages: primary infection;
clinical latency; and finally progression to AIDS (see
Fig. 3). The time interval between primary infection
and the development of AIDS is variable. For adults
in developed countries, it is on average lo-11 years
[115], however, about 20% of individuals will progress
in less than 5 years, while a few (< 5%) will remain
immunologically normal for over 10 years [1161. The
 GM Aldrovandi /Progress
biological basis for this variability is unclear but un-
doubtedly reflects differences in viral strains, host
immune responses and exposure to other cofactors
(microbial or environmental) especially those leading
to immune activation. The role of persistent virus
replication throughout the entire course of infection
has been established as a fundamental driving force
for disease pathogenesis [27-29,117]. During primary
infection, extremely high levels of plasma viremia
have been observed with levels of plasma RNA greater
than lo7 copies/ml [ 118-1201. These concentrations
will usually precipitously drop by 2 logs or greater
after several weeks. In 50-90% of cases this viremia
is symptomatic. After a period fluctuation of several
months, the level of plasma RNA stabilizes around a
so called ‘set point’ usually between lo3 and lo5
copies/ml (range < 200 copies to > 106). This level of
plasma viral RNA is a critical CD4 independent pre-
dictor of rapid progression to AIDS [121]. While there
is an inverse correlation between CD4+ cell count
and plasma RNA levels, at any CD4+ cell level there
is a wide inter-individual variation in plasma RNA
concentration [117,122]. The determinants of this set-
point are not yet understood but probably include the
effectiveness of host immune responses, the number
of available target cells, the degree of immune activa-
tion and the intrinsic pathogenicity of the infecting
strain. Irrespective of this initial set point, increasing
concentrations of plasma HIV RNA herald the devel-
opment of advancing immunodeficiency and AIDS
[122]. Likewise reduced concentrations of HIV-l RNA
Primary Infection Asympt omat ic
seroconvet sion
infect ion
I Plasma Viremia
CD4 count
HIV antibodies
[fi HIV specific
< >
4-6 weeks
Fig. 3. The natural history of HIV infection in adults.
in Pediatric Cardiology 7 (1997) 19-31 2.5
in response to anti-retroviral therapy are predictive of
improved prognosis [123].
Our understanding of the natural history of pedi-
atric HIV infection is still evolving. Viral dynamics
and cell turnover studies are in progress. Clinically, it
would appear that there are at least two patterns of
disease progression. About lo-20% of infected chil-
dren will develop profound immunosuppression, se-
vere encephalopathy, organomegaly, and multiple op-
portunistic infections in the first few months of life
[124,125]. Without treatment few of these children
survive more than 2 years. These children are far
more likely to have had HIV detected during the first
7 days of life [124] and have higher proviral loads
[126]. These rapid progressors are believed to have
been infected in utero. Presumably their fulminant
course is a consequence of uncontrolled viral replica-
tion in the face of a developing immune system.
However, all perinatally infected children have a worse
prognosis compared to adults (see Fig. 4).
Pediatric HIV infection has been classified by the
CDC as comprising four categories: stage N, no signs
or symptoms; stage A, mild signs or symptoms; stage
B, moderate signs or symptoms; stage C, severe signs
or symptoms [94]. All the AIDS-defining illnesses in
the 1987 CDC definition of pediatric AIDS are in-
cluded in stage C with the exception of LIP (lymphoid
interstitial pneumonitis) which is a B illness (see
Table 1). A summary of a recent analysis of the
clinical progression of over 2000 perinatally infected
children is presented in Fig. 4 [127]. Although this
Symptomatic AIDS
c
CTL 1 ,A< )
lo-12 years 2-3 years
 GM Aldrovandi /Progress in Pediatric Cardiology 7 (1997) 19-31

0 A: Mildly symptomatic

I- ~~ B: Moderately symptomatic

C: Severely symptomatic

I I I
I
0 10 14 79(6.6) 113(9.4)
Birth Death
Time in months (years)
Fig. 4. Mean age for clinical stages of perinatal HIV infection.

data has a number of potential biases toward en-
rolling more symptomatic children, it suggests that on
average children, progress to moderate symptoms in
the second year of life.
HIV infected children are also categorized on the
basis of the degree of immunosuppression [127]. In
adults, CD4+ cell level has proven to be a reliable
marker of the severity of immunosuppression, as well
as, determining the risk of developing certain oppor-
tunistic infections. For example, the risk of developing
Pneumocystis car&i pneumonia (PCP) increases dra-
matically at a CD4+ cell counts of 200 or less [128]. In
children the use of CD4+ cell counts is complicated
by the fact that they vary with age. In the first year of
life CD4+ cell counts are more than three times the
adult number and then gradually decline [129,130]. In
addition, children may develop opportunistic infec-
tions at higher CD4+ levels than adults [131]. The
current CDC classification system is based on age-
specific CD4+ counts and either the absolute CD4+
cell counts or the percentage of CD4+ lymphocytes
(see Table 2). If cell count and percentage place a
child in different categories it is recommended that
the more severe category be used.
Although the number of studies are still small, just
as in adult infection viral load appears to be the
critical determinant of pediatric disease progression.
One recent study [126] found that patterns of plasma
viral RNA kinetics in the first few months of life
correlated with disease course. Rapid progressors had
rapid increase in viral RNA which did not decline
while in more typical progressors the levels of RNA
declined [ 1261.
A small subset of persons infected with HIV ( < 5%)
are able to maintain normal CD4+ cell counts and
low viral loads for periods of greater than 12-15 years
without anti-retroviral therapy. They have been called
long-term survivors or long-term non-progressors
[132-1351. In adults, this appellation is usually defined
as those who have intact immune systems after more

Table 2
Age related changes in CD4 cell values

Age of child No evidence of immune Evidence of moderate Evidence of severe immune

suppression immune suppression suppression
CD4 no. %CD4 CD4 no. %CD4 CD4 no. %CD4
< 1 year 2 1500 r 25 750-1499 15-24 < 750 < 15
l-5 years 2 1000 225 500-999 15-24 < 500 < 15
6-12 years 2 500 2 25 200-499 15-24 < 200 < 15
 GM Aldrovandi /Progress in Pediatric Cardiology 7 (1997) 19-31
than 12-15 years. A few of these individuals appear
to be infected with less pathogenic variants of the
virus [37,136]. However, in most cases non-progres-
sion is believed to be due to immunogenetic factors
(see for a review [137]). The definition of a long-term
pediatric survivor includes those who have survived
longer than 8 years and unlike the adult definition,
permits inclusion of persons who have received anti-
retrovirals and are mildly symptomatic [138].
Pediatric centers that prospectively follow HIV ex-
posed children have described seroreverting infants
who had unexplained positive results [42,139], how-
ever, such cases were usually dismissed as laboratory
mistakes. One controversial case report claimed to
describe an infant who transiently had positive HIV
cultures and a positive PCR [140].
Studies of macaques infected with Simian Im-
munodeficiency Virus (SIV) would suggest that tran-
sient infection is possible. Infection with extremely
low levels of SIV or very attenuated strains can result
in transient infection [141]. How often this occurs in
humans and the virologic and immunologic factors
that govern this phenomena, have yet to be defined.
10. Current management of pediatric HIV infection
The management of children with HIV involves
treatment of not only the virus but the consequences
of immune dysregulation and destruction. Regular
monitoring of multiple organ systems, virological and
immunological parameters is necessary. The clinical
manifestations of HIV are protean, potentially af-
flicting every organ system. Our knowledge of how
best to treat infected children is rapidly evolving;
increasingly new antivirals, prophylactic regimens and
immunomodulatory agents are being tested and re-
leased. Given the complex nature of the disease and
the rapid advances in treatment, it is therefore not
surprising that a recent study of HIV infected adults
found a direct correlation between mortality and the
HIV experience of their treating physician [142].
Hence, the care of these children is best provided by
a specialized multi-disciplinary team.
Our greater understanding of the dynamics of HIV
infection coupled with availability of new anti-retro-
virals which decrease viral load by 2-3 logs, has led
many to advocate early aggressive treatment [143].
Viral diversity and high replication rates appears to
be fundamental to HIVs ability to escape the immune
system and anti-retrovirals. The relative homogeneity
of the viral quasispecies in early infection make it
more likely to respond to treatment since it would be
less likely to contain pre-existing drug resistant vari-
ants. An early decrease in the number of rounds of
replication would also markedly decrease viral diver-
sity. In turn, this could decrease the ability to escape
27
host immune response or develop resistance to anti-
retroviral agents. Effective reduction of viral load
early on, could also reset the viral set point and
thereby improve the subsequent clinical course. Pre-
liminary studies in the SIV system support this ap-
proach [144-1461. Studies are underway in adults to
test this hypothesis, however, perinatal HIV infection
is a near ideal situation in which to study early
therapeutic intervention. The source and timing of
infection can be readily identified and children have a
much greater capacity to regenerate T cells [147].
Armed with greater understanding of HIV pathogen-
esis and the an arsenal of potent anti-retrovirals,
there is now tremendous optimism that we will be
able to fundamentally alter the course of this fatal
disease and even cure it.
Acknowledgements
Grace Aldrovandi is a Scholar of the Pediatric Aids
Foundation.
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