Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice

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

doi:10.1016/j.xcrm.2023.101178

Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice

Cell Rep Med. 2023 Sep 19;4(9):101178. doi: 10.1016/j.xcrm.2023.101178. Epub 2023 Aug 30.

Authors

Philip Arandjelovic¹, Youry Kim², James P Cooney¹, Simon P Preston¹, Marcel Doerflinger¹, James H McMahon³, Sarah E Garner¹, Jennifer M Zerbato², Michael Roche⁴, Carolin Tumpach², Jesslyn Ong², Dylan Sheerin¹, Gordon K Smyth⁵, Jenny L Anderson², Cody C Allison¹, Sharon R Lewin⁶, Marc Pellegrini⁷

Affiliations

¹ Division of Infectious Disease and Immune Defence, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
² Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
³ Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.
⁴ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Emerging Infections Program, School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC, Australia.
⁵ Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, Australia.
⁶ Department of Infectious Diseases, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia; Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia; Victorian Infectious Diseases Service, The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
⁷ Division of Infectious Disease and Immune Defence, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia. Electronic address: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Disease Models, Animal
HIV Seropositivity*
HIV-1*
Humans
Mice

Substances

S63845
venetoclax
Bridged Bicyclo Compounds, Heterocyclic

Grants and funding

UM1 AI164560/AI/NIAID NIH HHS/United States