Chronic CD4+ T-Cell Activation and Depletion in Human Immunodeficiency Virus Type 1 Infection: Type I Interferon-Mediated Disruption of T-Cell Dynamics

Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of AIDS, which is a manifestation of the progressive CD4+ T-cell depletion that occurs in the setting of HIV-1 infection (19, 59). During acute infection by HIV-1, the process of CD4+ T-cell depletion is initiated by unchecked viral replication that occurs before an adaptive immune response is mounted (9, 19, 21, 45, 51, 59, 71, 77). Concomitant with development of a cytotoxic T-lymphocyte (CTL) response and the consequent reduction in viral replication, however, the CD4 count rebounds to a quasi-steady-state level that is below the baseline CD4 count of HIV-negative (HIV−) individuals and that decreases on the time scale of years (19, 59). In the gut-associated lymphoid tissue, where the majority of the body's lymphocytes reside, there is a dramatic depletion of CD4+ T cells during acute infection (9, 45, 51, 71, 77). However, AIDS develops only when CD4+ T cells have been sufficiently depleted that opportunistic infections occur (reflected by a CD4 count below 200 cells/μl). It is unclear how and why CD4+ T cells are depleted in the setting of chronic HIV-1 infection (19, 25, 28, 50, 59). The “tap and drain” model of CD4+ depletion during HIV-1 infection developed by Ho and colleagues suggests that the rate of CD4+ T-cell destruction by HIV-1 during chronic infection is too fast to be compensated for by natural CD4+ T-cell production (34). Consistent with the idea of increased destruction, CD4+ T cells from simian immunodeficiency virus (SIV)-infected macaques have been shown to have a substantially higher turnover rate than CD4+ T cells from uninfected macaques (30, 41, 52, 65). While more-recent studies continue to indicate a role for viral destruction (56) in CD4+ T-cell depletion, several important experimental observations suggest that factors in addition to destruction by viral infection are responsible for CD4+ T-cell depletion in the setting of HIV-1 infection. In particular, in both SIV-infected macaques and HIV-1-infected individuals, the majority of apoptotic CD4+ T cells are “bystander” cells rather than productively infected cells (20). Furthermore, the frequency of HIV-1-infected CD4+ T cells in humans is, on average, very low (14) and likely is too low if virus-induced death subsequent to infection is solely responsible for HIV-1-mediated CD4+ T-cell depletion (20), given known parameters of CD4+ T-cell dynamics in the setting of HIV-1 infection (2). Consistent with this observation, natural hosts of SIV, such as the sooty mangabey or African green monkey, do not exhibit a dramatic decline in the number of CD4+ T cells despite high viral loads similar to those observed in AIDS-susceptible nonhuman primate species, such as the rhesus macaque (38, 70). Chronic HIV-1 infection is characterized by massive and chronic activation of CD4+ T cells (29, 41, 63). This activation is reduced to near-normal levels by treatment with highly active antiretroviral therapy (HAART) (29) or in long-term nonprogressors (13). Interestingly, the level of CD4+ T-cell activation correlates better than the viral load with the degree of reduction in CD4 count in both HIV-1- and HIV-2-infected individuals (43, 54, 74). As with HIV-1, SIV induces excessive CD4+ T-cell activation in AIDS-susceptible species of nonhuman primates (e.g., rhesus macaques) but not in its natural hosts (e.g., the sooty mangabey or African green monkey) (70). These studies strongly suggest that massive and chronic CD4+ T-cell activation induced by HIV-1 infection plays a role in CD4+ T-cell depletion (25, 28, 50). However, several important questions remain unanswered. In particular, what is the mechanism through which chronic CD4+ T-cell activation leads to CD4+ T-cell depletion? Furthermore, what signals are acting on CD4+ T cells in the setting of HIV-1 infection (i) to induce such a substantial increase in activated CD4+ T cells and (ii) to modulate CD4+ T-cell depletion? In the present report, we describe a novel approach aimed at elucidating the molecular mechanisms through which chronic CD4+ T-cell activation in the setting of HIV-1 infection leads to CD4+ T-cell depletion. We hypothesized that if chronic CD4+ T-cell activation contributes to CD4+ T-cell depletion, then this pathogenic process should be reflected at the molecular level in the transcriptional profiles of activated CD4+ T cells of chronically infected HIV-positive (HIV+) individuals. Specifically, we wanted to determine whether there were qualitative differences in the activated CD4+ T cells from HIV-1-infected individuals compared to the activated CD4+ T cells from uninfected individuals. With this idea in mind, we carried out a microarray study of the gene expression profiles of activated CD4+ T cells from untreated, chronically infected HIV+ individuals with a comparison to activated CD4+ T cells from healthy HIV− individuals. We observed dramatic differences in patterns of gene expression in activated CD4+ T cells from infected versus uninfected individuals that lead to a new model for the role of chronic CD4+ T-cell activation in CD4+ T-cell depletion in the setting of HIV-1 infection.