TGFBR1 Blockade as Novel Release and Kill HIV Strategy

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ABSTRACT For many HIV infected people, lifelong combination antiretroviral therapy (cART) has converted the HIV epidemic from death sentence into a manageable chronic disease. However, the HIV reservoir persists in all treated individuals and viral rebound occurs upon cART interruption in the vast majority of patients. Given the challenges related to lifelong cART treatment such as adherence, viral escape, toxicity, and costs, finding novel ways to eradicate the virus and/or induce sustained virologic control in absence of cART is a very high priority in the HIV field. Tissues are major sites for HIV latency and notable contributors to viral rebound after cART interruption. TGF-β is an important immune suppressor factor, which orchestrates tissue immunity. Levels of TGF-β remain elevated in HIV infected individuals even after years of fully suppressive cART and contribute to immune suppression as well as to the development of non-AIDS-related, non-communicable disorders via pro-fibrotic mechanisms. TGF-β1 inhibits TCR-driven T cell proliferation and the maturation and function of other immune cell subsets. Importantly, TGF-β is currently being used to induce HIV latency in in vitro models of HIV latency in primary T cells. Our preliminary data demonstrate that blocking TGF-β signaling in vivo favors HIV latency reversal especially in tissues. Herein, we propose to test a novel latency reversal and immune stimulatory strategy based on the activity of a specific inhibitor of the TGF-β type I receptor (TGFBR1) in rhesus macaques. This strategy has given promising results in a pilot study in macaques and we propose to evaluate the effect of a prolonged administration similar to the regimen currently employed for cancer therapy. Moreover, we propose to determine the mechanism of action of the TGFBR1 inhibitor in vivo to better clarify its utility in the development of novel HIV cure strategies. Finally, we hypothesize that anti-HIV broadly neutralizing antibodies (bNAbs) may synergize with the TGFBR1 inhibitor in reducing the HIV reservoir and stimulate HIV-specific immune responses. Thus, we plan to perform a proof-of-concept study to determine the efficacy of combining the TGFBR1 inhibitor with bNAbs against SIV in SIV infected, cART treated rhesus macaques in reducing SIV reservoir and leading to virologic control after cART interruption. In summary, we propose the pre-clinical investigation of a novel TGFBR1 inhibitor that has the potential to be a powerful new addition to the toolbox of “shock and kill” HIV curative strategies.