Immunopathogenesis of HIV-1 Infection

Hiv Replication

Activated CD4 ⁺ T lymphocytes represent the main cellular target of HIV-1 and most of these cells reside in the gastrointestinal tract. During acute infection, adolescents and adults frequently have nonspecific “viral” symptoms (see Chapter 111 ) but infants usually are asymptomatic. In adolescents and adults, plasma viremia decreases and peripheral blood CD4 ⁺ T-cell counts increase after a few weeks even in the absence of ART. CD8 ⁺ cytotoxic T lymphocytes (CTLs) play a major role in this early control of viral replication. Additional adaptive immune responses as well as innate immune responses also play a role in the control of initial viral replication. Following this acute period, adults and older children have relatively constant levels of viremia, which is referred to as a “set point.” This level of viremia is highly predictive of the later course of disease progression. ^,

In contrast to older children and adults, HIV-1-infected infants have high levels of plasma viremia and do not achieve a “set point” for several years. These high and persistent levels of viremia are attributed to immunologic “immaturity.” ^, HIV-specific CTL responses can be detected at birth in infants infected in utero, but these responses are insufficient to control infection but may play a role the in slow progression observed in some children. ^, Studies suggest that this failure is due to decreased functional capacity, lack of CD4 ⁺ T-lymphocyte help and targeting of epitopes that inhibit the virus less effectively. ^, The relatively high frequency of regulatory T lymphocytes also may contribute to the suppression of viral specific T-lymphocyte responses. ^, Other immune factors that may play a role include a decreased capacity of neonatal natural killer cells to mediate antibody-dependent, cell-mediated cytotoxicity (ADCC).

The availability of increased numbers of target cells may also contribute to the high level of viremia. The absolute number and relative percentage of CD4 ⁺ T lymphocytes are much higher in infants and children. Relative to their body size, the mass of the thymus is increased and thymopoiesis is much more active during childhood than in adult life. Thus, a large renewable source of CD4 ⁺ T lymphocytes may serve as “fuel” for this infection and may account for the rapid tempo of disease progression observed in children. For these reasons, early initiation of ART is recommended and associated with decreased morbidity and mortality.

Immune Consequences of Untreated HIV-1 Infection

CD4 ⁺ T-lymphocyte depletion is the hallmark of HIV-1 infection. Direct infection leading to apoptosis by caspase-3 accounts for only 5% of this depletion. Approximately, 95% of CD4+ T lymphocytes die by caspase-1-mediated pyroptosis, a cellular defense mechanism in which non-productive fragments of HIV-1 genomic DNA activate a host DNA sensor resulting in formation of an inflammasome. The inflammasome fragments nuclear DNA, secretes interferon 1β (attracting other CD4+ T lymphocytes to their fiery death), and ruptures the cell. ^, Other potential mechanisms of CD4+ T-lymphocyte depletion include decreased production of bone marrow precursors and thymic dysfunction. The function and repertoire of the remaining CD4 ⁺ T lymphocytes are significantly perturbed resulting in defects in both B-lymphocyte antibody formation and the generation of effective CD8 ⁺ T-lymphocyte responses. Other immune cell perturbations in HIV-1 infection are shown in Box 110.1 .