Administration of Venetoclax to Promote Apoptosis of HIV-infected Cells and Reduce the Size of the HIV Reservoir Among People Living With HIV on ART

In summary, there is a compelling rationale for investigating venetoclax as an intervention to sensitise virus-expressing cells to apoptosis and thereby reduce the size of the latent HIV reservoir. While this concept may ultimately need to be tested in the setting of concomitant latency reversal, the investigators propose to initially establish the safety of venetoclax in PLWH on ART. The investigators will use this study to also investigate effects of venetoclax monotherapy on proapoptotic pathways, immune effector function and HIV persistence in PLWH on ART and through these studies establish the rationale for subsequent studies testing venetoclax in combination with an LRA.

Despite the great success of antiretroviral therapy (ART) in suppressing HIV replication, treatment for people living with HIV (PLWH) is lifelong and there is no cure. The main reason ART is unable to cure HIV is the persistence of HIV in a latent form in long-lived and proliferating CD4+ T-cells \[1\]. One strategy to eliminate latently infected cells, referred to as shock and kill, is by activating HIV expression in latently cells with the aim of eliminating infected cells through either virus-induced apoptosis or immune-mediated killing. This has been tested in several clinical trials using various latency-reversing agents (LRAs), but although these studies provided evidence that HIV latency can be disrupted in PLWH on ART, this did not lead to a reduction in the frequency of latently infected cells. Multiple studies have now demonstrated that not all infected cells that persist on ART have truly latent virus. In other words, residual low level transcription can persist on ART, measured as persistent detection of either cell associated HIV RNA or expression of p24 protein. These transcriptionally or translationally active cells are often more commonly found in tissue than in blood and is now referred to as the ''active reservoir''. For these cells, it is possible that expression of viral proteins could potentially either protect from or enhance cell death. It remains unclear why or how these cells can persist on ART, given their expression of viral proteins. A key barrier to effective elimination of infected cells, either the latent or active reservoir, may be a reduced susceptibility to killing of infected cells that persist on ART. Previous studies highlighted the considerable heterogeneity among subsets of CD4+ T cells in susceptibility to apoptosis \[8, 9\] and one study also showed that increased sensitivity to killing of infected cells may play a role in the exceptional control of HIV without ART seen in elite controllers \[10\]. By performing RNA sequencing of latently infected CD4+ T cells that survived co-culture with HIV-specific cytotoxic T cells (CTLs), Ren et al recently demonstrated that over-expression of the pro-survival factor B cell lymphoma 2 (BCL-2) is a prominent feature of cells that are resistant to killing and that the inducible HIV reservoir was disproportionately present in BCL-2hi CD4+ T cells.