BACKGROUND: HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART) as a long-lived viral reservoir. Recent evidence suggests that the viral reservoir is resistant to cell death as a result of up-regulation of anti-apoptotic molecules including B-cell lymphoma (BCL)-2. BH3-mimetics, such as venetoclax and other compounds, are small-molecule therapeutics which lower the threshold for induction of intrinsic apoptosis by antagonising the function of Bcl-2 family pro-survival proteins.
METHODS: We employed a humanized mouse model of latent HIV-1 infection, as well as CD4+ T cells from PLWH on ART collected by leukapharesis, to investigate whether antagonising host pro-survival proteins with clinically-relevant BH3-mimetics can preferentially prime latent cells to die and facilitate clearance of the viral reservoir. We quantified the time to viral rebound in humanized mice following cessation of ART and changes in the viral reservoir using either integrated DNA or the intact proviral DNA assay (IPDA). We performed RNA sequencing on venetoclax-treated CD4+ T cells from PLWH on ART.
RESULTS: Venetoclax, a clinically-approved inhibitor of Bcl-2, depleted total and intact HIV-1 DNA in CD4+ T cells from PLWH treated ex vivo in a dose-dependent manner (mean percentage decrease in intact DNA was 41.8% with 100 nM Venetoclax). Venetoclax induced higher rates of death in naïve and central memory T-cells, compared to other T-cell subsets. RNA-Seq analysis revealed that following venetoclax treatment ex vivo, cells with higher expression of transcripts of pro-apoptotic BH3-only proteins were over-represented. Venetoclax (dosed every weekday for 6 weeks) significantly delayed viral rebound following cessation of ART in a humanized mouse model of HIV-1 infection. The combination of venetoclax (dosed every weekday for 3 weeks) with the Mcl-1 inhibitor S63845 achieved a longer delay in viral rebound compared to either intervention alone (median time to viral rebound was 3 weeks).
CONCLUSIONS: Selective inhibition of pro-survival proteins, including BCL-2 and MCL-1, can induce elimination of the viral reservoir and prolong time to viral rebound after cessation of ART in a mouse model. Given the well-established dosage and safety profile of venetoclax in humans as a licensed drug, rapid translation to a human clinical trial of venetoclax is warranted.