Improving the "kick" in HIV "kick and kill" cure approaches

About This Grant

PROJECT SUMMARY Despite major advances in antiretroviral therapy (ART) treatment and distribution, latently infected “reservoir” cells remain a major barrier to developing a cure for human immunodeficiency virus (HIV) infections. Replication- competent HIV reservoirs are rare and remain stable for decades during ART, providing opportunities for viral rebound in the absence of ART. Multiple strategies have been explored in the field to eliminate or permanently silence HIV reservoirs, including the “kick and kill” cure approach. This two-pronged approach consists of inducing HIV reactivation from latency (kick) using a latency reversing agent (LRA), enabling a subsequent “kill” through immune mechanisms or viral cytopathic effects. However, no LRAs that completely reactivate all latent HIV have been identified, and the most successful introduce potentially harmful side effects such as proinflammatory cytokine induction. Thus, there remains a need to not only identify improved LRAs that balance HIV reactivation and immune activation, but also develop a greater understanding of the pathways involved in maintaining HIV latency. In this project, we propose to improve “kick and kill” LRAs through two approaches. Previous studies demonstrate protein kinase C modulators (PKC) are a particularly potent LRA class that strongly reverse HIV from latency but simultaneously induce high levels of proinflammatory cytokines upon activating T cells. Synthesized analogs of the natural PKC modulator bryostatin-1 have also been shown to possess improved tolerability and in vivo HIV reservoir reduction, highlighting the potential of optimizing compounds for the “kick and kill” approach. Building upon this, in Aim 1, we will evaluate promising next- generation PKC modulators for in vitro and in vivo latency reversal. To explore new molecular mechanisms of HIV latency, we propose to evaluate a novel polyadenylation-driven pathway using JTE-607, a small molecule with anti-inflammatory effects. In Aim 2, we will evaluate JTE-607 as a HIV LRA in vitro and in vivo and to complement strong but inflammatory PKC modulators by downregulating proinflammatory cytokine expression. By designing and working on this project, I will contribute enhanced LRAs that advance the “kick and kill” approach towards wider, safer implementation while enhancing fundamental knowledge of HIV gene regulation. Simultaneously, when completed, this project will yield improved HIV reservoir depletion strategies, complementing other cure approaches and bringing the field closer to a definitive HIV cure.