HIV Reservoirs In The Pathogenesis Of HIV Disease

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CD8+ T cell-mediated antiviral activity against HIV has been described consistently in infected individuals; however, the role of this activity in controlling replication of HIV in the latently infected, resting CD4+ T cell reservoir has been unclear. Using an ex vivo system, we examined the role of autologous CD8+ T cells in controlling HIV replication in this pool of cells relative to stage of disease and the status and timing of initiation of antiretroviral therapy. We demonstrated that replication of HIV in the latent CD4+ T cell reservoir was effectively suppressed by autologous CD8+ T cells in infected, untreated long-term nonprogressors (LTNPs) and in those patients whose viral replication was successfully controlled by HAART. In contrast, autologous CD8+ T cells suppressed virus replication to a much lesser extent in latently infected, resting CD4+ T cells from certain chronically infected patients who had substantial levels of plasma viremia. There was a lack of correlation between the capacity of autologous CD8+ T cells to suppress viral replication in the coculture setting and the overall frequency of HIV-specific CD8+ T cells in the peripheral blood compartment of these infected patients, suggesting that the mechanism of inhibition of HIV was independent of cytotoxic CD8+ T lymphocytes (CTL). When the antiviral role of soluble CD8+ T cell-derived factors was examined, we found that CC-chemokines played a major role in inhibition of viral replication in the latent CD4+ T cell reservoir in some LTNPs and in patients receiving HAART, but not in chronically infected patients who were not receiving antiretroviral therapy. Potent antiviral activity was exhibited by CD8+ T cell-derived soluble factors, other than CC-chemokines, and this activity was found mainly in infected individuals in whom HAART was initiated shortly after the acute phase of HIV infection. These results indicate that CD8+ T cells provide potent suppressive activity against HIV replication in the latently infected, resting CD4+ T cell reservoir via direct cellular contact, which is not dependent predominantly on CTL activity, and that this cell-mediated antiviral activity is most profound in patients who are naturally LTNPs or in those who are treated with HAART. Furthermore, soluble CD8 factors other than CC-chemokines showed the most profound suppressive activity against viral replication in the CD4+ T cell reservoir in infected patients who began HAART soon after the acute phase of HIV infection. These data suggest that preservation of this HIV-suppressive mechanism by early initiation of therapy may play an important role in containment of viral replication in infected patients following interruption of therapy.