Non-infected children born to
HIV-infected mothers are increasing worldwide due to
effective prevention of parent to child transmission of HIV
(PPTCT) programs. It is known that the use of highly active
antiretroviral therapy (HAART) reduces viral replication,
increases CD4+ T cell counts and decrease immune activation
and apoptosis in HIV-infected individuals [1]. The
introduction of antiretrovirals (ARVs) in HIV-infected
pregnant women has drastically decreased vertical
transmission of HIV. However, changes in both immunological
response and hematological parameters have been detected in
HIV-exposed uninfected newborns and attributed to both HIV
protein exposure in-utero as well as due to exposure to ARVs
for a prolonged time [2]. Further, mitochondrial dysfunction
in infants exposed to Nucleoside reverse transcriptase
inhibitors (NRTIs) has been reported in utero which
could lead to lactic acidosis [3,4]. Hematological changes
are often reversed soon but T-cell lymphocyte changes are
known to last even longer [2]. The paper by Wongnoi, et
al. [5] in the current issue highlights the important
aspect of hematological alterations and impaired thymic
function in newborns of HIV-infected mothers on ART.
HIV-1 specific immune responses have been
reported in children who have been exposed to the virus yet
remained uninfected leading to a state of immune activation
[6]. CD8+ immune responses to HIV-1 Env, Gag, and Nef
proteins have been shown in the peripheral blood of these
infants early after birth [7]. In addition HIV-1 specific
CD8+ interferon gamma responses have been detected in
HIV-exposed uninfected infants between 15-50 months of age
[8]. However, these studies were prior to use of maternal
HAART and is likely that these children were exposed to high
levels of maternal HIV viremia [7,8]. Even in children
exposed perinatally to HAART, HIV-1 specific immune
responses even in the setting of low maternal viremia leads
to low level of immune activation which is highest in the
cord blood and lower in the peripheral blood [6]. This may
be either due to infected maternal lymphocytes or activated
antigen presenting cells which may have microtransfused
across the placenta stimulating the fetal immune system [6].
Another immunological phenomenon observed is an increase in
B lymphocytes especially the CD19/CD5+ in cord blood of HIV
exposed newborns [2] with increased B cell apoptosis in
later life [6]. Therefore, these infants are still at an
increased risk for severe infections. A case series in South
Africa has reported eight HIV exposed uninfected children
who had unusual or severe infections, where their mothers
had received ARVs during pregnancy [9]. Lower CD4+ cell
count in cord blood has been reported due to low thymic
output [10]. Similarly, other markers for thymic output such
as T-cell receptor excision circles (TRECs) for CD4+ cells
have also been noticed to be lower in these children as
stated by the study by Wongkoi, et al. in this issue
[5]. Immune activation is known to recede over time;
however, lower CD4+ levels and higher B-cell apoptosis has
been noticed in older children 6-18 years of age who are
HIV-exposed but uninfected [10].
Several ARVs, most importantly Zidovudine
(AZT) and other NRTIs are known to cause anemia in adults
and children. Exposure to perinatal HAART is associated with
mild, reversible anemia in HIV-exposed uninfected children
[11]. In developing countries, the incidence and severity of
anemia may be greater due to micronutrient deficiency [12].
In children with limited exposure to AZT, the anemia is
usually microcytic whereas in children with prolonged
exposure to AZT (>6 months), the anemia is usually
macrocytic [13]. The explanation for the association of
maternal use of ARV during pregnancy and neonatal hemoglobin
levels is probably secondary to the reduced maturation of
the erythroid progenitor line in fetuses exposed to
medication [14].
In summary, HIV exposed uninfected
children have long term immunological changes due to either
in utero exposure to HIV proteins and also due to
exposure to ARVs. Anemia due to exposure to NNRTIs,
particularly AZT, is mild and reversible. Mitochondrial
depletion can lead to mitochondrial dysfunction that needs
to be evaluated further.
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