For the past several years, we have been investigating the role of latently infected, resting CD4+ T cells and persistent viral replication in the pathogenesis of HIV infection and the impact of this reservoir on the treatment of HIV-infected individuals. We previously demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all infected individuals receiving effective antiviral therapy. Consequently, this viral reservoir is a major impediment to the eradication of HIV in vivo. In addition, we realized that HIV continually replicates at low levels in chronically infected individuals who are receiving effective antiviral therapy that renders them consistently aviremic for prolonged periods of time. ? Over the past year, we have focused our research on: 1) investigation of the dynamics of persistent viral reservoirs in infected individuals who initiated antiviral therapy during the acute phase of HIV infection and 2) delineation of the mechanism by which HIV persists in infected individuals receiving effective antiviral therapy for extended periods of time. ? First, we conducted longitudinal measurements of the frequency of resting CD4+ T cells carrying replication-competent virus from a previously studied cohort of patients in whom antiviral therapy was initiated soon after primary infection and in whom viral replication was extremely well controlled by therapy. We demonstrated clear evidence for decay of latently infected, resting CD4+ T cells in infected individuals in whom antiviral therapy was initiated early in HIV infection. The half-life of this latent viral reservoir was estimated to be 4.6 months. It was projected that it will take up to 7.7 years of continuous therapy to completely eliminate latently infected, resting CD4+ T cells in infected individuals who initiate antiviral therapy early in HIV infection. ? Second, we investigated the presence and status of residual HIV in individuals who had received effective antiretroviral therapy for prolonged periods of time and we examined the underlying mechanisms by which HIV persists in CD4+ T cells of such individuals. We demonstrated that CD4+ T cells in the gut-associate lymphoid tissue (GALT) carried the highest level of HIV proviral DNA compared to CD4+ T cells in the blood of infected individuals receiving effective antiretroviral therapy for prolonged periods of time. Phylogenetic analyses of HIV env sequences (C2-V5) revealed active migration of virus between blood- and GALT-associated CD4+ T cells. ? Taken together, our data suggest that it may be feasible to eliminate HIV in the latent viral reservoir in HIV-infected individuals in whom effective antiviral therapy was initiated in the early phase of infection. Furthermore, our data also suggest that intensification of antiretroviral therapy, especially through the addition of newer classes of anti-HIV drugs, will be necessary to contain low levels of on-going viral replication in the tissue compartment of chronically infected individuals in order to achieve complete clearance of virus in vivo.
