Friday, April 19, 2024
4/19/2024
ABSTRACT Although anti-retroviral therapy (ART) slows disease progression, ART is a life-long therapy. Significantly, ART is not curative. It does not eliminate reservoirs of replication-competent virus. Thus, when ART is discontinued, HIV emerges from reservoirs and rapidly spreads, leading to disease progression towards AIDS. One strategy for clearing these reservoirs of latently infected cells, the principal if not sole source of continued infection, is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, allowing their subsequent “killing” or clearance by viral cytopathic effects, immune effector cells or additional therapies targeted at HIV- infected cells. To this end, we show proof-of-concept that a kick and kill strategy with uniquely effective latency reversing agents (LRA) and NK cells remarkably targets the HIV reservoir in a humanized mouse model, leading to a milestone of treatment interruption. Our next goal is to further enhance our kick and kill components to eradicate all replication-competent reservoirs of virus present during ART. We will design, synthesize, and investigate promising new compounds, the best kick components uncovered thus far, with the overall goal of producing superior LRAs and synergistic strategies that efficiently and safely purge the latent HIV in vivo. LRAs have been used to induce HIV expression from latent cells, but thus far have been limited by suboptimal efficacy, tolerability issues, and/or biodistribution concerns. Here, we address these problems using new LRA concepts and structures to improve efficacy, tolerability and control biodistribution. We investigate protein kinase C (PKC) modulators, which are the most potent and efficacious LRAs reported thus far. Within this family we have identified the best performers yet reported, inspired by bryostatin-1, prostratin and ingenol esters and new LRA scaffolds of the ingenane, tigliane, and epoxy-tigliane families. We have found that the chemical conversion of bryostatin-1 into a prodrug (slow-release) version results in a novel LRA with superior activity (60% v. 98%) and significantly improved tolerability (20-fold increase in therapeutic window). Thus, our goal is to advance this study of these new LRAs and chemically synthesized prodrugs using a highly collaborative team with expertise in novel computer-based design, synthesis, medicinal chemistry, state-of-the-art in vitro assays, and sophisticated in vivo animal modeling. To move this program toward clinical entry, optimal LRAs and prodrugs will be used in conjunction with a “kill” approach (natural killer cells) in humanized mice latently infected with HIV to assess the efficacy of the kick and kill strategy. We will accomplish our goals through the following Specific Aims: 1) Evaluate in vitro and in vivo new generation latency reversal agents based on new LRA scaffolds and their prodrugs, representing the most effective and best tolerated LRAs reported thus far, 2) Define and selectively activate PKC isoforms that enhance HIV latency reversal and improve tolerability, and 3) Develop new synergistic strategies to deplete the HIV reservoir. Collectively these studies will advance our unique and superior preclinical LRAs towards clinical testing.
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