MAJOR ARTICLE
HIV/AIDS
Human Immunodeficiency Virus (HIV)–Specific
Cellular Immune Responses in Newborns
Exposed to HIV In Utero
Louise Kuhn,1 Stephen Meddows-Taylor,2 Glenda Gray,3 and Caroline Tiemessen2
1
Gertrude H. Sergievsky Center, College of Physicians and Surgeons, and Division of Epidemiology, Joseph L. Mailman School of Public Health,
Columbia University, New York; 2AIDS Virus Research Unit, National Institute for Virology, Johannesburg, and 3Perinatal HIV Research Unit, Chris
Hani-Baragwanath Hospital, Soweto, South Africa
Significant immunological changes are associated with intrauterine human immunodeficiency virus (HIV)
encounter among uninfected infants of HIV-infected mothers. Peripheral blood cells of more than one-third
of these exposed-uninfected infants proliferate and produce IL-2 after stimulation with HIV, and HIV-specific
CD4+ T helper cell responses can be quantified in nearly all when sensitive intracellular cytokine assays are
used. HIV-specific CD8+ cytotoxic T lymphocyte responses can be elicited in some, although less frequently.
It is difficult to demonstrate that these responses are components of protective immunity and not simply
epiphenomena of exposure. However, HIV-specific responses are associated with lack of infection, even with
prolonged reexposure through breast-feeding. Elevations in nonspecific markers of immune activation provide
further corroboration, as do similar findings in adults, consistent across all known routes of HIV transmission.
Many questions remain, but much can be learned from this special population that may be informative for
development of effective immunity in response to HIV vaccines.
It has intrigued the scientific community that kinds of
apparently HIV-specific anamnestic cellular immune
responses can be detected in individuals exposed to HIV
but who remain uninfected [1, 2]. Uninfected infants
of HIV-infected mothers are a special case of such an
exposed-uninfected population and offer a unique opportunity to investigate the significance of these observations. Even in the absence of antiretroviral drugs,
most infants of HIV-infected mothers (65%–85%) do
not acquire HIV infection. However, a proportion of
uninfected infants may have been sensitized or primed
to HIV in utero. We review herein studies that have
investigated this phenomenon and evaluate the extent
Received 3 May 2001; revised 15 August 2001; electronically published 7
December 2001.
Reprints or correspondence: Dr. Louise Kuhn, Columbia University, Sergievsky
Center, 630 W. 168th St., New York, NY 10032 ([email protected]).
Clinical Infectious Diseases 2002; 34:267–76
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3402-0020$03.00
to which the responses identified can be thought to be
true components of protective immunity.
FREQUENCY OF HIV-SPECIFIC IMMUNE
RESPONSES AMONG EXPOSEDUNINFECTED CHILDREN
Cellular immune responses to HIV antigens can be elicited among more than one-third of infants born to
HIV-infected mothers (table 1). One of the earliest
studies to report apparently HIV-specific responses
among uninfected children measured lymphocyte proliferation after stimulation with recombinant HIV proteins [3]. Later, several groups elicited cytotoxic T lymphocyte (CTL) responses to HIV epitopes among
uninfected children [4–8], but at least 1 group has not
confirmed this [9]. One study used an epitope based
on the father’s genotype, not shared by the mother, to
rule out maternal contamination [5]. Because detection
of CTL to HIV in an uninfected individual is an unexpected finding on its own, the focus has been on
HIV/AIDS • CID 2002:34 (15 January) • 267
Table 1. Studies describing HIV-specific cellular immune responses in peripheral blood and cord blood from uninfected
infants of HIV-infected mothers.
Site, reference
USA [3]
HIV-specific
response, no. (%)
11 (37)
Age range with
positive responses
Type of response
measured
Antigens generating positive responses
Not given
Lymproliferation
Recombinant envelope and core proteins
France [4]
3 (100)
2–35 months
CTL
HLA-A1, A2, A3 env, gag, and nef
England [5]
1 (100)
5 months
CTL
HLA-B8 gag
Scotland [6]
2 (18)
6–17 months
CTL
Vaccinia tat pol
Italy [7]
6 (26)
15–50 months
CTL
Vaccinia gag nef, pol, env
USA [8]
2 (22)
6–17 months
CTL
Vaccinia env
USA [9]
0
1–18 months
CTL
Vaccinia env gag
USA [10]
8 (40)
Cord blood
IL-2 production
Synthetic envelope peptides
South Africa [11]
28 (42)
Cord blood
IL-2 production
Envelope peptides
6 (86)
Cord blood
IL-2 mRNA
Envelope peptides vaccinia gag nef, pol, and env
2 (22)
Cord blood and
1–12 months
CTL
Italy [13]
14 (93)
Mean, 31 days
Intracellular cytokine (CD4⫹
IL-2⫹ T cells)
3 (38)
Mean, 31 days
CD8⫹ IFN-g in
Envelope peptides
USA [15]
16 (52)
1 months–5 years
CD8⫹ anti-HIV response
Non–HLA-restricted, non–b-chemokine–mediated
suppression of HIV replication
USA [12]
NOTE.
Envelope peptides
CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen.
thorough documentation of small numbers of cases, rather than
on attempts to accurately quantify its prevalence in well-defined
cohorts. Hence, the proportion of exposed-uninfected infants
with HIV-specific CTL responses is not accurately known. Children have been studied opportunistically at a wide range of
ages and investigation confined to children with human leukocyte antigen (HLA) genotypes for which epitopes are
available.
An alternative approach has measured, after stimulation with
HIV peptides, production in mononuclear cells of IL-2, a type
1 cytokine and 1 of the primary effectors in CD4⫹ T helper
cell responses. Cord blood leukocytes from 8 (40%) of 20 exposed-uninfected infants produced IL-2 after stimulation with
synthetic HIV envelope peptides in 1 study [10] and 28 (42%)
of 67 in another [11]. Measurement of IL-2 mRNA after stimulation with envelope peptides, which is a more sensitive
method, detected anti-HIV responses in nearly all (6 of 7) HIVexposed-uninfected infants [12]. Comparison of responses in
cord versus maternal blood ruled out maternal contamination
[10, 12]. HIV-stimulated IL-2 production has not been detected
among any infants of uninfected mothers [10, 11].
New developments in methods for measuring intracellular
cytokine production, which allow the percentage of HIV envelope-stimulated IL-2–positive CD4⫹ T lymphocytes to be directly quantified by flow cytometry, have greatly strengthened
these observations. Almost all (14 of 15) exposed-uninfected
infants at a mean age of 31 days had HIV-specific CD4⫹ T
lymphocytes [13]. HIV-stimulated IFN-g production by CD8⫹
T lymphocytes was detected in only 3 of 8 exposed-uninfected
infants and only among those with the highest number of HIV268 • CID 2002:34 (15 January) • HIV/AIDS
specific CD4⫹ T lymphocytes [13]. The predominance of helper
cell responses was previously noted in the cohort that detected
HIV-stimulated IL-2 mRNA among 6 of 7 exposed-uninfected
infants but CTL responses among only 2 of 9 infants [12].
Although a key function of helper cell responses is to direct
and empower CTL, in the case of protection against HIV infection, helper cell responses may be markers for other underlying processes. In one report, envelope-stimulated b-chemokine production was significantly elevated among
exposed-uninfected infants [12]. The role of b-chemokines and
their receptors is a critical area for further research [14].
Another unconventional anti-HIV immune response, that of
CD8⫹ noncytotoxic antiviral activity, has been observed among
16 of 31 exposed-uninfected children [15]. This response was
measured by suppression of acute infection in vitro of a fastreplicating, b-chemokine–insensitive, cytopathic laboratory
strain of HIV in HLA-mismatched CD4⫹ cells. Children of a
wide age range were studied, but responses were more common
and stronger among children aged !1 year [15].
A potential concern is that presumed exposed-uninfected
subjects with HIV-specific responses are, in fact, infected. Studies have differed in their rigor to rule out infection (none, for
instance, have ruled out infection confined to lymph nodes).
This explanation is unlikely, however, given the high frequency
of these responses, which is inconsistent with well-established
expectations about transmission rates.
At least 1 cycle of intracellular replication is assumed to be
necessary to induce CTL, which suggests that, at least where
CTL can be elicited, exposure involved live, replicating virus
and implies that an infection may have been cleared. Interest
developed around reports of apparently transient or abortive
infections in which HIV was cultured or viral DNA amplified
(once or many times) among exposed infants who, on repeated
testing, turned out not to have detectable HIV infection or
clinical disease [16–20]. In 1 well-documented case, thorough
attempts were made to rule out laboratory error by HLA and
HIV genotyping [20]. In a later report of 43 suspected cases
of transient HIV infection almost all were found to be due to
mislabeling or contamination, casting doubt that viral clearance
was a real phenomenon [21]. However, if abortive infection is
brief and transient, sometimes occurs in utero, and may be
with a virus of low replication competency, unequivocal demonstration of viral clearance may be an almost impossible task.
The role of exposure to defective virus, viral antigens, or soluble
viral proteins may be more relevant. Priming without an active
infection would support the hypothesis of non-CTL–mediated
mechanisms.
NONSPECIFIC IMMUNE RESPONSES
IN HIV-EXPOSED–UNINFECTED CHILDREN
Nonspecific immune responses observed among exposed-uninfected infants corroborates significant HIV exposure. Elevations in populations of activated helper T cells (CD4⫹HLADR⫹CD38⫹) and memory helper T cells (CD4⫹CD45RA⫺RO⫹)
have been observed among exposed-uninfected infants [13, 22].
Soluble L-selectin, shed after lymphocyte activation by antigenpresenting cells, has been observed to be higher among exposed-uninfected infants in the first 2 days of life, although
this did not reach statistical significance [23]. Transient expansions in the T cell receptor b-chain variable region of exposeduninfected infants have also been observed [24]. Each of these
observations suggest prior antigenic stimulation greater than
that among uninfected pregnancies.
Reduced IL-12 production in cord blood was observed
among infants of HIV-infected mothers, which suggests potentially immunosuppressive effects of in utero HIV exposure
even among the uninfected [25]. Cord blood IL-12 was correlated with maternal IL-12, pointing to influence of maternal
immune status on fetal immune development [25]. Reduced
IL-2 [22] and elevated IFN-g and IL-10 has been observed
among exposed-uninfected infants [26]. The inference that
these differences in nonspecific responses can be attributed to
HIV exposure is limited, given that HIV-infected and -uninfected women may differ in many characteristics—for example,
other intercurrent infections, which may influence the intrauterine environment.
Few studies have specifically tested, in experimental systems
or in quasi experimental observational studies, whether these
unconventional immune responses confer protection against
primary HIV infection. The obvious inability to perform a
human challenge study does not preclude use of other study
designs, such as prospective epidemiological studies. These
types of studies can examine naturally occurring exposures and
can provide stronger evidence than the circumstantial evidence
available to date.
PROTECTION OR EPIPHENOMENON?
Taken together, these findings clearly demonstrate that past
encounters with HIV are of immunological significance. However, it has yet to be clearly demonstrated that any of these
responses are truly protective against primary infection and not
simply epiphenomena of HIV exposure. Rather than signifying
protective immunity, the responses may simply be coincidental
markers of exposure.
The putative protective role of HIV-specific cellular immune
responses is often justified on the basis of their role in controlling (in the absence of antiretroviral treatment) viral replication and clinical decline among individuals already infected.
CTL responses are detectable soon after infection and, if they
are persistent, strong and broad antigenicity are associated with
a better prognosis [27–30]. Vigorous HIV-specific helper T cell
responses are observed among long-term nonprogressors
[31–33] and correlate negatively with virus load [31, 32, 34].
Nonspecific T cell function declines quantitatively and qualitatively with HIV disease progression [34–36], and loss of T
cell function is one of the strongest immunologic predictors of
mortality in chronically infected individuals [37]. Most studies
are of adults, and pediatric infection may differ in several important respects. Nevertheless, the most important limitation
of this substantial body of literature (well reviewed elsewhere
[38]) is that it does not necessarily follow that immunological
processes once an individual is already infected are similar to
processes that occurred prior to infection. Critical distinctions
between HIV-specific responses in the infected versus in the
exposed but uninfected need to be clarified.
PROTECTION AGAINST SUBSEQUENT
EXPOSURE? VALUE OF BREAST-FEEDING
POPULATION
The context of maternal-infant HIV transmission offers a window of opportunity to test the putative protection of immune
responses. Intrauterine HIV exposure elicits apparently HIVspecific responses in some infants [10, 12]. Subsequent HIV
exposure occurs intrapartum during which some, but not all,
infants acquire infection. Transmission through each of these
routes can be quantified with reasonable precision [39, 40]. At
least 2 studies have observed associations between detection of
responses to HIV peptides at birth and lack of infection [10,
12] with kinetics and levels of HIV-specific cellular immune
HIV/AIDS • CID 2002:34 (15 January) • 269
responses among infected (increasing after birth) and uninfected (decreasing after birth) infants, consistent with protective
immunity [12].
The situation in which infants of HIV-infected mothers are
breast-fed is more informative since it offers an opportunity
to perform a kind of natural human challenge study. Among
a cohort of infants born to HIV-infected mothers enrolled in
a study in Durban, South Africa, IL-2 production in cord blood
leukocytes was measured, as described elsewhere [10, 41], after
stimulation with a cocktail of synthetic HIV envelope peptides
[42–44]. Envelope-stimulated IL-2 production was detected
among more than one-third of infants of HIV-infected mothers
but among no unexposed control subjects. Just under 10% of
infants with envelope-specific responses had HIV RNA detected
in venous blood collected on the day of birth, which implies
intrauterine transmission. Those not already infected were followed prospectively to quantify the subsequent risk of transmission through intrapartum routes and breast-feeding (twothirds were breast-fed). None of the infants responsive to HIV
envelope peptides in cord blood was found to be HIV-infected
on subsequent tests, whereas 17% of infants unresponsive to
envelope peptides acquired HIV infection intrapartum or postpartum (P p .02) (figure 1). Responses to non-HIV antigens
were not associated with transmission [11].
Although that study offered a rigorous test of the hypothesis
that 1 type of HIV-specific response is protective, few infections
could be definitively attributed to breast-feeding, because early
breast-feeding infections cannot easily be distinguished from
intrapartum infections by use of standard diagnostic tests
[45–47]. Because infants were reexposed to virus from the same
source (their mother) that primed the initial response, the study
provided no test that the response would protect against exposure from a different source (particularly relevant to sexual
transmission) or that it would provide any long-term benefits
extending beyond the postnatal months over which breast-feeding took place. It also cannot rule out confounding by some
third factor. However, the observation was not explained by
other known risk factors for transmission, including maternal
parameters (plasma virus load, CD4 counts, CD4 : CD8 ratios,
serum retinol, and clinical status), infant parameters (prematurity and low birth weight), or delivery characteristics (mode
of delivery and duration of membrane rupture).
LESSONS LEARNED FROM OTHER HIV
EXPOSED-UNINFECTED POPULATIONS
HIV-specific cell-mediated responses, like those observed
among infants of HIV-infected mothers, have been demonstrated among other exposed-uninfected populations, including
gay men reporting unprotected sexual exposure [48, 49], injection drug users [50], male and female sex partners of HIV270 • CID 2002:34 (15 January) • HIV/AIDS
Figure 1. Evidence of lower risk of intrapartum and breast-feeding
HIV transmission associated with HIV envelope–stimulated IL-2 production
in cord blood leukocytes. Shown are the Kaplan-Meier probability curves
of detecting HIV RNA by the age (up to 1 year) among 59 breast-fed
infants born to HIV-infected mothers stratified by their HIV-stimulated
response in cord blood. No mothers were treated with antiretroviral drugs.
IL-2 production in cord blood leukocytes was measured after stimulation
with HIV envelope peptides by bioassay. Those with stimulation indices
13 were considered responsive to envelope, and those with stimulation
indices !3 were considered unresponsive [11].
infected individuals [51–61], commercial sex workers in communities of high-prevalence HIV [62–65], and health care
workers with occupational HIV exposures (table 2). Consistency across all known routes of transmission supports the link
with HIV exposure. Either single percutaneous or repeated mucosal exposure appears to be sufficient. The concept that resistance to HIV can be acquired is most strongly supported by
studies among commercial sex workers and gay men repeatedly
exposed to HIV from many sources over many years, because
with increasing exposure, it becomes increasingly less likely that
they escaped infection by chance or by failure to encounter
virus of sufficient infectivity [62].
From the studies in adults, it appears that detection of HIVspecific immune responses is not a sufficient condition for
protection against infection. One of the first reports of helper
T cell responses to HIV was in a man who had detectable virus
and HIV antibody production just over 1 year later [49]. This
does not preclude a role for these responses in quantitatively
reducing transmission risk but implies that the responses are
markers only and that underlying processes are still to be
identified.
HIV-specific humoral immune responses (IgA to specific
gp160 epitopes) in cervical secretions [68–71] have been detected in uninfected women with sexual exposure to HIV, which
suggests compartmentalization of immune responses with dif-
Table 2. Studies describing HIV-specific cellular immune responses in peripheral blood among uninfected adults
exposed to HIV.
Site, reference
No. (%) with
HIV-specific
response
Source of HIV exposure
Gay men with repeated, recent unprotected sexual HIV exposure
Italy [50]
Injection drug-users at high risk
Finland [51]
Male sexual partners of HIV-infected men
USA [52]
Heterosexual partners of HIV-infected individuals
France [53]
Heterosexual partners of HIV-infected individuals
Israel [54]
Ethiopian immigrants sexual partners of HIV-infected individuals
Italy [55]
Heterosexual partners of HIV-infected individuals
9 (82)
Lymphoproliferation
Germany [56]
Sex partners of HIV-infected individuals
5 (45)
TNF-a
USA [57]
Repeated high-risk sexual exposure
Canada [58]
Sex partners of HIV-infected individuals
USA [59]
Repeated high-risk sexual exposure
6 (100)
Type of response
USA [48, 49]
16 (76)
IL-2 production
IL-2 production
5 (36)
Lymphoproliferation
18 (60)
Lymphoproliferation
6 (100)
23 (66)
16 (46)
CTL
IL-2 production
CD8⫹ noncytotoxic
anti-HIV activity
7 (41)
CTL
13 (36)
CTL
4 (11)
Lymphoproliferation
Canada [60]
Sex partners of HIV-infected individuals
5 (45)
CTL
Switzerland [61]
Heterosexual partners of HIV-infected individuals
2 (25)
CD4⫹ intracellular IFN-g
Kenya [63]
Sex workers repeatedly exposed to HIV
7 (41)
IL-2 production
15 (68)
CTL
Sex workers repeatedly exposed to HIV
3 (50)
CTL
Kenya [65]
Sex workers repeatedly exposed to HIV
10 (48)
USA [66]
Health care workers with occupational injuries involving HIV-infected blood
6 (75)
IL-2 production
USA [67]
Health care workers with occupational injuries involving HIV-infected blood
7 (35)
CTL (confirmed HLA
class I restricted)
Gambia [64]
21 (75)
NOTE.
CTL (memory-specific)
IL-2 production
CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen.
ferent mechanisms operating at the mucosa and in the periphery. CD8⫹ lymphocyte–mediated IFN-g responses to CTL
epitopes have also been detected [70, 72]. Mucosal immune
responses have not been investigated in children, in part because of lack of clarity concerning the relevant mucosal site of
viral entry.
of gastric and oropharyngeal aspirates from newborns of HIVinfected mothers, which demonstrates ingestion of HIV-containing maternal fluids during birth [81–84]. Although detection of virus in these samples is correlated with transmission,
most infants with detectable virus in these samples are uninfected [81–84].
HOW DOES VIRUS EXPOSURE TAKE PLACE?
CAUSES OF PROTECTIVE IMMUNE
RESPONSES
In the case of infants of HIV-infected mothers, detection of
HIV-specific responses in cord blood implies that encounter
with HIV occurred in utero, because exposure at delivery would
not have had enough time to elicit a specific response. That
intrauterine HIV contact occurs is supported by studies that
have detected HIV in fetal tissue from elective and spontaneous
terminations [73–76]. Placental trophoblasts [77] and macrophages (Hofbauer cells) [78] are susceptible to infection with
HIV in vitro. HIV can be amplified from chorionic villi from
the majority of term placentas of HIV-infected women, even
after exclusion of maternal contamination [79, 80].
Contact with HIV also occurs during delivery, where there
is direct and prolonged contact with maternal cervicovaginal
secretions and blood. HIV DNA can be detected in 30%–40%
We know very little about characteristics of the virus, the host,
or the encounter that result in one individual developing a
potentially successful immune response to HIV, whereas another does not. One explanation may be the dose of exposure.
Macaques inoculated with doses of simian immunodeficiency
virus (SIV) below the threshold required for seroconversion
exhibited T cell proliferation to SIV peptides and, when subsequently challenged with higher SIV doses, did not become
infected. Animals never previously exposed to SIV all became
infected [85]. No association, however, was observed between
maternal virus load during pregnancy and HIV-stimulated IL2 production among uninfected infants [11]. This observation
may be uninformative, because the assumption that HIV RNA
HIV/AIDS • CID 2002:34 (15 January) • 271
copy numbers in maternal plasma measures the dose of virus
to which the infant is exposed is probably incorrect.
Host genetic factors may be important. Different HLA types
may modify the efficiency of HIV antigen presentation or may
interact with viral epitopes to generate successful cellular immune responses. A creative approach has considered not only
the host’s genotype but the interaction with the genotype of
the viral source. A study in Nairobi, Kenya, observed concordance between mothers and children in class I HLA alleles to
be associated with greater risk of perinatal HIV transmission.
Mother-child pairs concordant at all 3 class I HLA loci (6 of
6 HLA-A, -B, and -C alleles) were more likely to transmit (31%
of infants infected) than pairs in which only 3 of 6 alleles were
concordant (3% of infants infected) [86]. Whether discordance
facilitates priming of HIV-specific responses or whether it plays
a protective role via some other mechanism is unknown.
CONSEQUENCES OF ANTIRETROVIRAL
TREATMENT
Maternal-infant HIV transmission can be substantially reduced
with antiretroviral drugs [87], even when given in short perinatal regimens [88–90]. The mechanisms responsible for the
benefits are unclear, because the anticipated mechanism, that
of drug-induced suppression of maternal virus load, accounts
for only a small proportion of the reduction in transmission
[91]. Effects of antiretroviral drug regimens on newborn immune function are important to investigate.
In 1 study of HIV-infected pregnant women treated with
short-course combinations of zidovudine-lamivudine in Soweto, South Africa, HIV envelope peptide–stimulated IL-2 production in cord blood leukocytes was reduced 110-fold compared with that in cord blood from HIV-infected untreated
women [92]. These findings are puzzling, because although
antiretroviral drugs could theoretically have reduced HIV from
maternal blood and other fluids, effectively reducing antigenic
exposure, all women on treatment had levels of HIV RNA in
plasma at delivery well above the threshold of detection. The
effects of the drugs were dramatic, even when they were started
only shortly before delivery (figure 2). In at least 1 other exposed-uninfected population (health care workers with occupational exposures to HIV), reductions in HIV-specific responses were observed with postexposure prophylaxis with
zidovudine [93].
PERSISTENCE OF HIV-SPECIFIC RESPONSES
The persistence of HIV-specific responses in infants has not
been well described. HIV-specific responses could be detected
in exposed-uninfected infants up to age 6 months [11, 92] but
could not by age 7 years [13]. It is assumed that HIV-specific
272 • CID 2002:34 (15 January) • HIV/AIDS
Figure 2. Reduced HIV-stimulated IL-2 production in cord blood leukocytes from infants of HIV-infected mothers treated with antiretroviral
drugs. Shown are the stimulation indices quantifying the amount of IL2 produced after stimulation with HIV envelope peptides among group
1, HIV-infected mothers not treated with any antiretroviral drugs during
pregnancy or peripartum; group 2, HIV-infected mothers treated with
zidovudine-lamivudine started only at the onset of labor; group 3, HIVinfected mothers treated with zidovudine-lamivudine at ∼36 weeks gestation; and group 4, HIV-uninfected control mothers [92].
responses wane without antigenic restimulation. This may be
valid for infected individuals in whom reduction of circulating
virus with potent antiretroviral treatment eliminates HIV-specific immune responses [94]. Viral rebound, associated with
treatment interruptions, particularly in those with primary infection, boosts HIV-specific responses. Augmentation of HIVspecific cellular immune responses with this form of “immunization” appears to be effective enough in some individuals
to control viral replication without antiretroviral therapy
[95–97]. These observations highlight the complexity of demonstrating whether HIV-specific responses are protective given
the dynamic interplay of host and virus over time in which
exposure is both a possible source of potentially protective
sensitization and the origin of infection.
DEVELOPMENTAL CONTEXT
The development of HIV-specific cellular immune responses
among uninfected infants of untreated HIV-infected mothers
is especially noteworthy given the well-known immaturity of
T cell function in the fetus and neonate [98]. Human cord
blood cells proliferate poorly and are poor producers of type
1 cytokines when stimulated with recall antigens or with antigens requiring autologous antigen presenting cell function
[99, 100] . Lack of extensive prior exposure to antigen and the
predominance of T cells of naive phenotype may in part, but
not fully [101], account for the deficits [102]. The deficits can
be overcome under the right conditions. Neonatal T cells appear to have a greater requirement for strong costimulatory
signals to generate functionally mature responses [102, 103].
The maternal environment may play a crucial role in this to
influence the nature of the fetal response after antigenic exposure [25, 99].
There is some precedent from other infections for the detection of antigen-specific cellular immune responses in the
absence of infection, notably that of human T-lymphotropic
virus type 1 [104]. Cellular immune responses to hepatitis C
antigens have been detected in exposed-uninfected adults [105,
106]. Their existence implies that processes occurring with HIV
may not be unique.
6.
7.
8.
9.
10.
11.
CONCLUSIONS
Understanding HIV-specific immunity in infants of HIV-infected mothers is important for interventions to reduce transmission through this route, either to supplement existing antiretroviral drug regimens or to target routes more difficult to
reach with drugs, such as transmission through breast-feeding.
That there are data to support the notion that, among infants
exposed to HIV in utero, at least one-third develop seemingly
protective cellular immune responses bodes well for development of effective vaccines that could be used among infants.
Preliminary vaccine studies suggest the feasibility of vaccines
in the neonatal population. Two recombinant gp160 vaccines
have been tested among HIV-infected and -exposed infants and
were found to be safe [107–109]. Modest lymphoproliferative
responses could be observed in approximately one-half of those
vaccinated. Maternal-infant HIV transmission offers an informative natural exposure setting in which both viral source and
recipient are identifiable and transmission can be quantified
over a well-defined time frame. It will be important to learn
from this setting which parameters are relevant to protection,
to better inform the development of effective interventions.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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