Article
Author: Lim, U-Ming ; Zuck, Paul ; Li, Yuan ; Rothman, Deborah M. ; Schwaid, Adam G. ; Cornella-Taracido, Ivan ; Fang, Zhiyu ; Xu, Min ; Song, Cheng ; Carroll, Steven S. ; Bahnck-Teets, Carolyn ; Rodriguez, Silveria ; Adam, Gregory C. ; Anand, Rajan ; Lammens, Alfred ; Tudor, Matthew ; Andrews, Christine L. ; Park, Sangho ; Lan, Ping ; Howell, Bonnie J. ; Moningka, Remond ; Lusen, Jeffrey ; Lu, Meiqing ; Sun, Wanying ; Hollenstein, Kaspar ; Beshore, Douglas C. ; Moore, Keith P. ; McHale, Carolyn ; Shipe, William D. ; Converso, Antonella ; Chi, An ; Diamond, Tracy L. ; Li, Jing ; Quan, Shuo ; Goh, Shih Lin ; Klein, Daniel J. ; Fay, John F. ; Filzen, Tracey ; Balibar, Carl J.
Although current antiretroviral therapy can control HIV-1 replication and prevent disease progression, it is not curative. Identifying mechanisms that can lead to eradication of persistent viral reservoirs in people living with HIV-1 (PLWH) remains an outstanding challenge to achieving cure. Utilizing a phenotypic screen, we identified a novel chemical class capable of killing HIV-1 infected peripheral blood mononuclear cells. Tool compounds ICeD-1 and ICeD-2 ("inducer of cell death-1 and 2"), optimized for potency and selectivity from screening hits, were used to deconvolute the mechanism of action using a combination of chemoproteomic, biochemical, pharmacological, and genetic approaches. We determined that these compounds function by modulating dipeptidyl peptidase 9 (DPP9) and activating the caspase recruitment domain family member 8 (CARD8) inflammasome. Efficacy of ICeD-1 and ICeD-2 was dependent on HIV-1 protease activity and synergistic with efavirenz, which promotes premature activation of HIV-1 protease at high concentrations in infected cells. This in vitro synergy lowers the efficacious cell kill concentration of efavirenz to a clinically relevant dose at concentrations of ICeD-1 or ICeD-2 that do not result in complete DPP9 inhibition. These results suggest engagement of the pyroptotic pathway as a potential approach to eliminate HIV-1 infected cells.