BCL-2 antagonism sensitizes cytotoxic t cell-resistant hiv reservoirs to elimination ex vivo

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T-cells that persists despite HIV-specific cytotoxic T-cell (CTL) responses. While viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified over-expression of the pro-survival factor BCL-2 as a distinguishing feature of CD4+ T-cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets, in ex vivo CD4+ T-cells. Treatment with the BCL-2 antagonist 'ABT-199' alone was not sufficient to drive reductions in ex vivo viral reservoirs, when tested either alone or with a latency reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.