BCL-2 Antagonism Sensitizes CTL-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 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. We explored the hypothesis that this resistance is mediated by BCL-2 family proteins, which can antagonize CTL-induced apoptosis. We show that the reactivatable HIV reservoir is disproportionately present in BCL-2hi CD4+ T-cells, which are relatively resistant to CTL. BCL-2/BCL-XL antagonists were sufficient for inducing the elimination of HIV-infected cells from a primary-cell model of latency, but did not drive reductions in ex vivo viral reservoirs when tested either alone or with a latency reversing agent (LRA). The triple combination of LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled depletions in ex vivo viral reservoirs, providing rationale for novel therapeutic approaches targeting HIV cure.