Multi-Omics Correlates of Therapeutic Vaccine Efficacy

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SUMMARY The goal of therapeutic vaccination is to increase host immune control of HIV-1 to achieve durable virologic control in the absence of ART, which is defined as a “functional cure”. However, therapeutic vaccine studies in humans have to date been largely unsuccessful. In contrast, in previous therapeutic vaccination studies in SIV/SHIV infected non-human primates (NHPs), a subset of animals achieved viral control including reduced viral levels in lymphoid organs, suggesting an anti-reservoir effect of the interventions. Understanding the mechanisms underlying therapeutic vaccine efficacy and identifying immune signatures that associate with anti- reservoir activity in vivo is a fundamental prerequisite towards their optimization for HIV cure. In Project 2, we hypothesize that combinatorial immunization strategies that result in virological control induce unique peripheral and tissue immune signatures, including reorganization within viral tissue reservoirs, which can be identified using spatial multi-omics approaches. We further hypothesize that such protective immune responses mediate their efficacy primarily in lymphoid tissues. To evaluate these hypotheses, we propose two Specific Aims: Aim 1. Identify the immunological correlates of virologic control in SIV/SHIV-infected rhesus macaques following active and combinatorial immunization strategies. We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing specimens from three non-human primate and one clinical studies study to generate hypotheses regarding correlates of long term vs. short term virologic control. Aim 2. Define mechanisms of peripheral and tissue viral reservoir control in lymphoid tissues following therapeutic vaccination of SHIV-infected rhesus macaques. We will perform interventional studies to test the hypothesis that combinatorial vaccine strategies can induce immune responses that target the viral reservoir in lymph nodes and gastrointestinal mucosa in SHIV-infected rhesus macaques. We will apply cutting-edge, high-throughput, multi-omics profiling platforms detailed in Core B (Multi-Omics Core) to define the impact of therapeutic vaccination. We will then integrate the multi-omics data in Core C (Computational Analysis Core) to generate a comprehensive landscape and regulatory network of the viral reservoir and host immune responses following therapeutic vaccination. These data will define the impact of therapeutic vaccination on the replication-competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next generation HIV-1 cure efforts.