Venetoclax, Alone and in Combination with the BH3 Mimetic S63845, Depletes HIV-1 Latently Infected Cells and Delays Rebound in Humanized Mice

Overview

Journal Cell Rep Med

Publisher Cell Press

Specialties Biology
General Medicine

Date 2023 Aug 31

PMID 37652018

Authors

Philip Arandjelovic

Youry Kim

James P Cooney

Simon P Preston

Marcel Doerflinger

James H McMahon

Sarah E Garner

Jennifer M Zerbato

Michael Roche

Carolin Tumpach

Jesslyn Ong

Dylan Sheerin

Gordon K Smyth

Jenny L Anderson

Cody C Allison

Sharon R Lewin

Marc Pellegrini

Affiliations

Soon will be listed here.

Abstract

HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4 T cells from PLWH on ART, we investigate whether antagonizing host pro-survival proteins can prime latent cells to die and facilitate HIV-1 clearance. Venetoclax, a pro-apoptotic inhibitor of Bcl-2, depletes total and intact HIV-1 DNA in CD4 T cells from PLWH ex vivo. This venetoclax-sensitive population is enriched for cells with transcriptionally higher levels of pro-apoptotic BH3-only proteins. Furthermore, venetoclax delays viral rebound in a mouse model of persistent HIV-1 infection, and the combination of venetoclax with the Mcl-1 inhibitor S63845 achieves a longer delay in rebound compared with either intervention alone. Thus, selective inhibition of pro-survival proteins can induce death of HIV-1-infected cells that persist on ART, extending time to viral rebound.

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