ABSTRACT 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 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 in the context of novel active latency reversing agents, immunomodulatory approaches to directly kill reactivated cells through antiviral antibodies and increased sensitivity to apoptosis will reduce viral reservoirs and thus maintain suppression of virus replication following cessation of anti-retroviral drugs. The approaches summarized in FOCUS 1 of the aims below 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 heterologous SHIV challenge. In FOCUS 2 we will utilize novel latency reversing agents and CD8+ T cell depletion to define an optimal reactivation program, and then will combine these with the antiviral monoclonal antibodies and inhibitors of BCL-2 to explore the potential of this combination to yield a sustained suppression of virus replication following cART withdrawal. These experimental approaches will be supported by 5 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. This supplement application for this comprehensive program has two specific aims. In Aim 1 (FOCUS 1), we will test the synergy between functional antibody response and tissue resident T cells in providing long-term protection against a heterologous tier-2 intravaginal clade C SHIV challenge. In Aim 2 (FOCUS 2), we will test if a combination of a cocktail of anti-SIV monoclonal antibodies and a compound, venetoclax, shown in vitro to sensitize reservoir cells to apoptosis help to reduce viral reservoirs in the setting of potent reversal of viral latency. Results from these studies will have important implications for the development of effective preventive vaccines and cure strategies for HIV.