A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates ex xivo Reservoirs from Patients

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 thus failed in clinical study. 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 PZ703b's potential in clinical HIV cure strategies. This  approach may pave the way for novel therapeutic interventions aimed at eliminating the HIV-  inducible reservoir.

Note:
Funding Information: This research was supported by the NIH under grant number 2R56AI104416-11A1.

Declaration of Interests: Each author declares no conflicts of interest.

Ethical Approval Statement: This protocol was approved by the Columbia University institutional review board. All participants provided written informed consent.

Keywords: Shock and Kill Strategy, Latency-reversing agents (LRAs), Bcl-2/Bcl-xL dual degraders, HIV reservoir eradication, Functional cure of HIV.