Project 2: Analysis of Reservoir Dynamics in SIV-Infected Rhesus Macaques

摘要-项目二

Summary – Project 2 Non-human primate (NHP) models have provided valuable insights into HIV-1 pathogenesis, prevention, and treatment. Of particular importance are models involving infection of rhesus macaques with SIV or SHIV. With respect to viral reservoirs, we have previously shown that widespread SIV dissemination and reservoir seeding take place in the first few days of infection. The Barouch lab have also explored cure strategies in rhesus macaques, focusing on immune stimulating agents, therapeutic vaccination, broadly neutralizing antibodies, and combinations of these approaches. These studies have provided some promising early evidence of effects on viral rebound and post-treatment control. The Siliciano lab provided early evidence that latently infected resting CD4+ T cells in blood, lymph nodes, and spleen are an important reservoir in SIV-infected macaques. Available studies on reservoir dynamics in SIV-infected macaques suggest an overall similarity to reservoir dynamics in PLWH. In the studies proposed here, we will capitalize on the advantages of NHP models to explore the establishment, composition, and dynamics of the latent reservoir. The studies are designed to extend the studies in PLWH proposed in Project 1 and address critical questions in reservoir dynamics that cannot be easily addressed in humans. The Specific Aims of this project are: Specific Aim 1. To define the cell types responsible for the first and second phases of decay of viremia following initiation of ART. We hypothesize (1) that most of the plasma virus is produced by a rapidly decaying population of activated CD4+ T cells present in the lymph nodes and other lymphoid tissues, (2) that the 2nd phase of decay reflects the elimination of a distinct population of CD4+ T cells in a lower state of activation that produce virus for a longer period of time, and (3) that the 2nd phase represents selection process that shapes the composition and dynamics of the stable latent reservoir. Specific Aim 2. To determine the mechanism by which infected cells are eliminated during the first and second phases of decay. Using CD8 depletion experiments, we will test the hypothesis that the elimination of 2nd phase cells is mediated by virus-specific CTL.