B and T Cell Biology of Protection from and Eradication of SIV/SHIV Infection

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 DESCRIPTION (provided by applicant): The Emory Consortium for Innovative AIDS Research in Nonhuman Primates aims to understand the B and T Cell Biology of Protection from and Eradication of SIV/SHIV Infection. The consortium brings together an interdisciplinary mix of highly collaborative, and productive investigators in a range of HIV vaccine and cure disciplines to address the overarching hypothesis that a successful prophylactic HIV vaccine will require a strong and sustained systemic and mucosal immune response, comprised of functionally targeted antibody and tissue resident CD8 T cell immunity, in concert with a modulated HIV-specific CD4 T cell response that maintains low numbers of HIV targets in mucosal tissue, while providing adequate help for a strong adaptive response. Moreover, we postulate that such a potent and balanced vaccine response will, in the context of active latency reversing agents, reduce viral reservoirs and thus maintain suppression of virus replication following cessation of highly active antiretroviral therapy. The approaches in FOCUS 1, aimed at understanding the mechanisms of vaccine protection, will utilize state of the art adjuvants coupled with native trimeric Env immunogens to induce and mechanistically dissect strong durable humoral responses. In addition, we aim to fully characterize and harness a novel population of tissue resident CD8 T cells to effectively synergize with the humoral immune response in providing protection from SHIV challenge. Because recent data suggest that SIV/HIV specific mucosal CD4 T cells could enhance infection, we will also explore the potential for modulating the susceptibility of these cells to enhance protection. In FOCUS 2, aimed at defining mechanisms of reservoir eradication, we will utilize novel latency reversing agents and immunostimulants to define an optimal viral reactivation program, and then will combine these with the optimized vaccine approaches defined in FOCUS 1 to explore the potential of this combination to yield a sustained suppression of virus replication following withdrawal of highly active antiretroviral therapy. These experimental approaches will be supported by an effective Operations and Management Support component and five state of the art Scientific Research Support Cores in order to fully characterize the magnitude, function, specificity and repertoire of the humoral response. Single cell analytics and transcriptomics will also support characterization of innate and adaptive signals at the cellular level.