The effect of combining HIV latency reversal with inhibition of phosphoinositide-3 kinases or B-cell lymphoma-2 on the HIV reservoir

The persistence of latently infected CD4 + T-cells in people with HIV (PWH) on suppressive antiretroviral therapy (ART) is the major barrier to an HIV cure. We investigated the impact of two classes of pro-apoptotic drugs, phosphoinositide-3 kinases (PI3K) inhibitors or the B cell lymphoma 2 (Bcl-2) inhibitor venetoclax on depletion of latently infected CD4 + T-cells when administered ex vivo either alone or in combination with a latency reversing agents (LRA) to induce expression of pro-apoptotic viral proteins. We quantified cell death in three latently infected cell lines (J-Lat clones) and the parental cell line (Jurkat) using a live dead stain and flow cytometry. Using CD4 + T-cells isolated from blood from PWH on ART, we quantified intracellular HIV RNA, integrated HIV DNA and intact proviral DNA using quantitative PCR. In the Jat10.6 latently infected cell line, the combination of an LRA with either a PI3K inhibitor or venetoclax, compared to an LRA alone resulted in higher levels of cell death. Using CD4 + T-cells from PWH on ART, there was a significant decrease in HIV DNA following administration of wortmannin (a pan-PI3K inhibitor), venetoclax (a Bcl2 inhibitor) and JQ1 (an LRA) when administered alone. There was minimal additional effect on reservoir reduction following the addition of an LRA with a pro-apoptotic drug, compared to either an LRA or pro-apoptotic drug alone. However, when CD4 + T-cells from PWH on ART were treated with LRAs combined with a PI3K inhibitor, the fold increase in cell associated unspliced HIV RNA correlated with the decline in HIV DNA. Overall, reduction in the HIV reservoir by LRAs could be further enhanced in the presence of pro-apoptotic drugs, but the magnitude of the effect was modest, was dependent on the in vitro model used and for PI3K inhibitors, depended on the potency of latency reversal. These results are consistent with minimal additional efficacy in reservoir reduction when combining currently available LRAs and either PI3K inhibitors or venetoclax.