Multi-Omics Correlates of Broadly Neutralizing Antibody Efficacy

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SUMMARY Accumulating data suggests that administration of broadly neutralizing antibodies (bNAbs) in ART-suppressed, SHIV-infected nonhuman primates (NHPs) and HIV-1-infected humans can delay viral rebound following ART discontinuation. However, the mechanism underlying the efficacy of bNAbs remains to be determined. Multiple mechanisms may contribute to the effectiveness of bNAbs in delaying viral rebound, including direct antiviral activity against replicating virus, targeting of the replication-competent viral reservoir, and indirect effects such as augmenting cellular immune responses via the “vaccinal” effect. Understanding the mechanism of action underlying bNAb efficacy will lead to optimization of these and other HIV-1 cure strategies. In Project 1, we hypothesize that bNAbs can directly target the viral reservoir in addition to providing direct antiviral effects, both of which contribute to the observed long-term virologic control following ART discontinuation. An alternative hypothesis is that bNAbs contribute to long-term antiviral efficacy by modulating host cellular immunity via the vaccinal effect. To evaluate these hypotheses, we propose two Specific Aims: Aim 1. To determine multi-omics correlates of bNAb based virologic control in HIV-1-infected humans. We will perform a comprehensive virologic, immunologic, and multi-omics analysis of existing clinical specimens from the T003 study to generate hypotheses regarding correlates of long term vs. short term virologic control. Aim 2. To define mechanisms of bNAb efficacy in lymphoid tissues in SHIV-infected rhesus macaques. We will perform interventional studies to test the hypothesis that bNAbs can 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 bNAb therapy. 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 bNAb therapy. These data will define the impact of bNAbs on the replication- competent viral reservoir at an unprecedented level of resolution, which will provide critical insights for next generation HIV-1 cure efforts.