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

Authors:

• Arandjelovic, Philip
• Kim, Youry
• Cooney, James P.
• Preston, Simon P.
• Doerflinger, Marcel
• McMahon, James H.
• Garner, Sarah E.
• Zerbato, Jennifer M.
• Roche, Michael
• Tumpach, Carolin
• Ong, Jesslyn
• Sheerin, Dylan
• Smyth, Gordon K.
• Anderson, Jenny L.
• Allison, Cody C.
• Lewin, Sharon R.
• Pellegrini, Marc

Details:

Cell Reports Medicine, Volume 4, Issue 9, 2023-09-19

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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.