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Mechanisms to Therapeutics: TACK Molecules Kill HIV-Infected Cells Through Inflammasome Activation: "potential to cure HIV via reduction in viral reservoir" ?
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CROI 2024 March 3-6 Denver
Tracy L. Diamond
Merck & Co, Inc, Rahway, NJ ,USA
Background: The viral reservoir, consisting of both HIV-1–expressing and latently infected cells, necessitates life-long antiretroviral therapy (ART) to suppress HIV-1 replication in people living with HIV (PLWH). Current ART blocks viral replication and prevents spread to healthy cells. In doing this it maintains, but does not reduce, the HIV infected cell reservoir. A common approach to address the reservoir is known as "shock and kill", which seeks to reactivate latent HIV-1 such that cells can be targeted and eliminated through viral cytolysis or host cellular immunity. This approach has yielded some clinical success in inducing viral reactivation but has had little to no impact on reducing the reservoir. Cytotoxic agents that are selective for HIV-infected cells could enhance or complement such a strategy. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are common components of ART that have been designed to enzymatically block the viral reverse transcriptase (RT), however studies have demonstrated that some NNRTIs also have a secondary mechanism of action resulting in HIV-specific cell kill. Through this targeted activator of cell kill (TACK) mechanism NNRTIs enhance HIV-1 Gag-Pol dimerization causing premature HIV-1 intracellular protease maturation which induces HIV-1 cytotoxicity through CARD8 inflammasome activation. Although current marketed NNRTIs have potent RT inhibitory activity, they contain weak to no secondary TACK activity and therefore are not expected to be relevant inducers of HIV-cell kill at clinical exposures. Here, we optimized this secondary activity to identify TACK compounds with potencies compatible with clinically achievable concentrations. Pre-clinical proof of concept for cell kill was demonstrated in ex vivo studies with cells from PLWH as well as in an HIV-infected humanized mouse model. These novel NNRTI-TACK molecules have a potential application in HIV cure via reduction in the viral reservoir.
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