More than forty million individuals worldwide are infected with human immunodeficiency virus type 1 (HIV-1). Highly active antiretroviral therapy (HAART) improves survival, but the complex regimen must be lifelong due to persistence of HIV-1 in viral reservoirs (resting CD4+ T cells) and in plasma (viremia). The Vaccine Research Center (VRC) at the NIH and the Pediatric AIDS Clinical Trials Group (PACTG) will soon begin multi-center clinical trials testing a therapeutic vaccine approach as an adjunct to HAART to enhance HIV-1 specific immunity, perhaps allowing eventual treatment discontinuation or simplification. However, vaccines' impact on viral reservoirs and viremia is unknown. We propose to test the hypothesis that a therapeutic vaccine approach, given as an adjunct to HAART, will facilitate decay of viral reservoirs and viremia due to enhanced HIV-1 specific immune responses. Using samples from two clinical trials of HIV-1 vaccine strategies as an adjunct to effective HAART in young adults, we propose measuring and tracking over time the vaccines' effect on 1) the extent of the latently infected CD4+ T cell reservoir; 2) the level of viremia; and 3) the genetic composition of the viral reservoir and viremia. Enhanced virus culture methods we developed will be used to assess decay of replication-competent HIV-1 in resting CD4+ T cells. Sensitive molecular methods for detecting plasma virus below 50 copies/ml will be used to measure changes in low-level viremia. Shifts in the genetic composition of the CD4+ T cell reservoir and viremia will be analyzed using phylogenetic methods we previously used to link reservoir and viremia HIV-1 variants. Clinical specimens and analytic resources from VRC and PACTG provide a unique opportunity to study pathogenesis of viral reservoirs in HIV-1 infected individuals. ? ? ?
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