Enhanced latency reversal and reservoir clearance in macaques

About This Grant

New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. This key obstacle to cure HIV consists of a reservoir of latently infected CD4+ T cells that persist despite long-term antiretroviral therapy (ART) and cause rebound of viremia if ART is interrupted. The R37 award AI157862 “Enhanced latency reversal and reservoir clearance in macaques” was funded in July 2021 with the overarching objective to obtain a deeper and broader understanding of the latency reversal induced by a SMAC mimetic (SMACm) and its potential to reduce persistent reservoirs using an innovative “kick and kill” approach. We have learned that treatment of SIV-infected, ART-suppressed macaques with the SMACm AZD5582, that activates the ncNF-kB signaling pathway, reactivates rebound competent latent reservoirs throughout the body. We also learned that the combination of AZD5582 and the BCL-2 inhibitor venetoclax reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ART interruption. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. We have three priority areas for the next phase of this R37 award that build on our body of work using venetoclax as well as broadly neutralizing antibodies (bNAbs), that have both antiviral and pro-immune effects. First, focus on reservoir establishment as an optimal time to intervene (rather than the maintenance phase). Second, focus on the antiviral immunity needed to complement venetoclax as a reservoir reducing intervention. And third, a deep dive into how the spatial landscape and immunovirologic features of infection are influenced by venetoclax. Our Central Hypothesis is that bNAb therapy will synergize with promotion of infected cell apoptosis through BCL-2 inhibition to limit reservoir formation. Using our expertise in conducting rigorous in vivo studies in nonhuman primates and immunovirologic multiomic analyses, we will test our hypothesis in three Specific Aims: 1) Define how venetoclax combined with bNAb therapy during early ART impacts decay of viremia, the intact reservoir, and the spatial landscape of infection; 2) Determine how venetoclax combined with bNAb therapy during early ART influences antiviral immune responses in a tissue-specific context; 3) Evaluate the virologic and immunologic impact of venetoclax and bNAb therapy given at start of ART versus at ART interruption. The experiments proposed will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed. Our experiments will evaluate safety and efficacy in a preclinical model. We hope that the results we generate will contribute to a cure for people living with HIV. RELEVANCE (See instructions): New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. The goal of our research program is to identify targeted immunotherapies that reduce HIV reservoir formation when given early in infection with antiretroviral treatment. Our experiments will evaluate safety and efficacy in a preclinical model to inform approaches to cure HIV.