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

Chang, Lin-Chun, Yin, Michael T., Laird, Gregory M., Ritter, Kristen D., Shah, Jayesh G., Debnath, Asim K.·2025·International Journal of Molecular Sciences
DOI 10.3390/ijms26062772PMC PMC11942780
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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 and thus failed in clinical study. In this study, we repurposed PZ703b, a pro-apoptotic protein degrader initially developed for anti-leukemia therapy, to target HIV eradication. PZ703b induced the degradation of Bcl-2 and Bcl-xL, activating the non-canonical NF-kB pathway and caspases cascade, resulting in latency reversal and the selective apoptosis of infected cells. The treatment of ex vivo CD4+ T cells from ART-suppressed HIV-1 patients led to approximately a 50% reduction in the replication-competent reservoir. While this result does not reach the threshold required for a complete cure, it demonstrates the potential of a dual degrader of Bcl-2/Bcl-xL in reversing HIV latency and inducing selective cell death. Our study provides a proof-of-concept for using dual degraders of Bcl-2/Bcl-xL as a novel category of LRAs in therapeutic strategies aimed at reducing HIV reservoirs. This approach may pave the way for the further exploration of targeted interventions to eliminate the HIV-inducible reservoir.

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Metadata

Authors
Chang, L.-C., Yin, M. T., Laird, G. M., Ritter, K. D., Shah, J. G., & Debnath, A. K.
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2025-03-19
Volume
26
Issue
6
Pages
2772
ISSN
1422-0067
DOI
10.3390/ijms26062772
PMC
PMC11942780
Cited by
3
References
7
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
NIH (2R56AI104416-11A1)

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