Chemical Inhibition of DPP9 Sensitizes the CARD8 Inflammasome in HIV-1-infected Cells

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2022 Nov 10

PMID 36357533

Authors

Kolin M Clark

Josh G Kim

Qiankun Wang

Hongbo Gao

Rachel M Presti

Liang Shan

Affiliations

Soon will be listed here.

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.

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