Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1
Carl J. Balibar, Daniel J. Klein, Beata Zamlynny, Tracy L. Diamond, Zhiyu Fang, Carol Cheney, Jan Kristoff, Meiqing Lu, Marina Bukhtiyarova, Yangsi Ou, Min Xu, Lei Ba, Steven S. Carroll, Abdellatif El Marrouni, John F. Fay, Ashley Forster, Shih Lin Goh, Meigang Gu, Daniel J. Krosky, Daniel I. S. Rosenbloom, Payal R. Sheth, Deping Wang, Guoxin Wu, M. Zebisch, Tian Zhao, Paul Zuck, Jay A. Grobler, Daria J. Hazuda, Bonnie J. Howell, Antonella Converso
Abstract
Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1–infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase–p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 + cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 + T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.