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

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ABSTRACT The Emory Consortium for Innovative HIV/AIDS Vaccine and Cure Research in Nonhuman Primates aims to define the mechanisms of the B and T Cell Biology of Protection from and Eradication of 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 the success of the prophylactic HIV vaccine we have developed during the current program is due to a combination of a strong and sustained systemic and mucosal immune response. This is comprised of multi-functional antibody and tissue resident CD8 T cell immunity, which upon encountering cognate antigen responds through conventional cytolytic mechanisms and through modulation of the mucosal environment, such that responding HIV-specific CD4+ T cell are resistant to infection. 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 techniques and analyses to fully characterize and harness a novel population of tissue resident CD8 T cells induced by our Heterologous Viral Vector vaccine (HVV vaccine) encoding Gag as an immunogen to effectively synergize with the humoral immune response induced by our HIV envelope trimer vaccine (Protein vaccine) co-delivered with novel adjuvants to provide long-term protection against heterologous SHIV challenge even in the absence of strong neutralizing antibody response. In the later years we will use this novel, mechanistic information to optimize the vaccine and move it closer to clinical studies. In FOCUS 2 we will pursue, in SHIV-infected ART-treated macaques, the “shock and kill” approach to induce virus expression from latently infected cells using latency reversal agents (LRAs) following therapeutic vaccination aimed at boosting virus- specific immune responses able to clear CD4 T cells in which virus production has been reactivated. First, will determine how the HVV+Protein vaccine behaves in ART suppressed macaques and then study its ability to deplete the reservoir in the context of active LRAs and its impact on control of viral rebound. These experimental approaches will be supported by an effective Operations and Management Support component and three state of the art Centralized Research Resources to fully characterize the magnitude, function, specificity and repertoire of the humoral response. Single cell analysis and transcriptomics will also support characterization of innate and adaptive signals at the cellular level.