A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs

Abstract

The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. The "shock and kill" strategy involves reversing latency with latency-reversing agents (LRAs) and selectively inducing cell death in infected cells. However, current LRAs have shown limited efficacy in eliminating the ex vivo HIV reservoir. We repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and selective apoptosis of infected cells. Treatment of ex vivo CD4+ T cells from ART-suppressed HIV-1 patients achieved a [~]50% reduction in the replication-competent reservoir. Our study provides proof-of-concept for using protein degraders to reverse HIV latency and induce cell death, highlighting PZ703bs potential in HIV cure strategies. This approach may pave the way for novel therapeutic interventions aimed at eliminating the HIV-inducible reservoir.