@article{f0bcfc07a5464e4b82a549a66632c78d,
title = "Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells",
abstract = "Non-nucleoside reverse transcriptase inhibitors (NNRTIs) induce pyroptosis of HIV-1-infected CD4+ T cells through induction of intracellular HIV-1 protease activity, which activates the CARD8 inflammasome. Because high concentrations of NNRTIs are required for efficient elimination of HIV-1-infected cells, it is important to elucidate ways to sensitize the CARD8 inflammasome to NNRTI-induced activation. We show that this sensitization can be achieved through chemical inhibition of the CARD8 negative regulator DPP9. The DPP9 inhibitor Val-boroPro (VbP) can kill HIV-1-infected cells without the presence of NNRTIs and act synergistically with NNRTIs to promote clearance of HIV-1-infected cells in vitro and in humanized mice. More importantly, VbP is able to enhance clearance of residual HIV-1 in CD4+ T cells isolated from people living with HIV (PLWH). We also show that VbP can partially overcome NNRTI resistance. This offers a promising strategy for enhancing NNRTI efficacy in the elimination of HIV-1 reservoirs in PLWH. [Figure not available: see fulltext.]",
author = "Clark, {Kolin M.} and Kim, {Josh G.} and Qiankun Wang and Hongbo Gao and Presti, {Rachel M.} and Liang Shan",
note = "Funding Information: We thank the volunteers who participated in this study, and L. Kessels, M. Klebert, A. Haile, T. Spitz and T. Minor for study subject recruitment. We thank Regeneron Pharmaceuticals and the Richard Flavell Laboratory at Yale University for generating the human cytokine knock-in mice. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: rilpivirine, efavirenz, lopinavir, etravirine, nevirapine, maraviroc, T-20, tenofovir, raltegravir, pNL4-3-GFP, international HIV-1 isolates and HIV-1 p24 antibodies. Funding in support of this work was provided by NIH grants nos. R01AI162203 and R01AI155162 (L.S.) and F31AI165251 (K.M.C.). The organizations that supplied these funds had no part in the planning or execution of the work presented in this study. Funding Information: We thank the volunteers who participated in this study, and L. Kessels, M. Klebert, A. Haile, T. Spitz and T. Minor for study subject recruitment. We thank Regeneron Pharmaceuticals and the Richard Flavell Laboratory at Yale University for generating the human cytokine knock-in mice. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH: rilpivirine, efavirenz, lopinavir, etravirine, nevirapine, maraviroc, T-20, tenofovir, raltegravir, pNL4-3-GFP, international HIV-1 isolates and HIV-1 p24 antibodies. Funding in support of this work was provided by NIH grants nos. R01AI162203 and R01AI155162 (L.S.) and F31AI165251 (K.M.C.). The organizations that supplied these funds had no part in the planning or execution of the work presented in this study. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = apr,
doi = "10.1038/s41589-022-01182-5",
language = "English",
volume = "19",
pages = "431--439",
journal = "Nature Chemical Biology",
issn = "1552-4450",
number = "4",
}