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 Aug 23;101178. doi: 10.1016/j.xcrm.2023.101178.
Philip Arandjelovic  1 ,  Youry Kim  2 ,  James P Cooney  1 ,  Simon P Preston  1 ,  Marcel Doerflinger  1 ,  James H McMahon  3 ,  Sarah E Garner  1 ,  Jennifer M Zerbato  2 ,  Michael Roche  4 ,  Carolin Tumpach  2 ,  Jesslyn Ong  2 ,  Dylan Sheerin  1 ,  Gordon K Smyth  5 ,  Jenny L Anderson  2 ,  Cody C Allison  1 ,  Sharon R Lewin  6 ,  Marc Pellegrini  7
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].
PMID: 37652018 DOI: 10.1016/j.xcrm.2023.101178
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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