Cell reports medicine
Highlights
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Venetoclax delays viral rebound in a humanized mouse model of HIV infection
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Venetoclax depletes intact HIV DNA ex vivo in cells from people living with HIV on ART
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The HIV reservoir is enriched in cells with higher expression of BH3-only proteins
Summary
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.
Graphical abstract
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Introduction
Although antiretroviral therapy (ART) suppresses HIV-1 replication, pro-virus can persist in long-lived and proliferating CD4+ T cells and is the likely source of rapid viral rebound when ART is interrupted.
Persistence of HIV-1 on ART necessitates lifelong treatment and represents the key obstacle to cure. Despite early optimism, it is apparent that transcriptional reactivation of latently infected cells is not sufficient to induce cell death and delay viral rebound,
and recent evidence suggests that antiapoptotic mechanisms are in place that maintain survival of latently infected cells despite the highly apoptotic environment of productive infection.
BH3 mimetics are small-molecule therapeutics that lower the threshold for induction of intrinsic apoptosis by antagonizing the function of Bcl-2 family pro-survival proteins.
Venetoclax is a BH3 mimetic that specifically antagonizes Bcl-2 and is approved for the treatment of chemotherapy-refractory chronic lymphocytic leukemia (CLL).
While the ability of venetoclax to kill latent and productively infected cells in vitro has been explored by others, we sought to examine the efficacy of venetoclax in a physiologically relevant in vivo model of HIV-1 persistence on ART and in CD4+ T cells from people living with HIV (PLWH) on ART.
Venetoclax is a BH3 mimetic that specifically antagonizes Bcl-2 and is approved for the treatment of chemotherapy-refractory chronic lymphocytic leukemia (CLL).
While the ability of venetoclax to kill latent and productively infected cells in vitro has been explored by others, we sought to examine the efficacy of venetoclax in a physiologically relevant in vivo model of HIV-1 persistence on ART and in CD4+ T cells from people living with HIV (PLWH) on ART.