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

49 Pages Posted: 21 Nov 2024 Publication Status: Review Complete

See all articles by Lin-Chun Chang

Lin-Chun Chang

New York Blood Center

Michael Yin

Columbia University - Aaron Diamond AIDS Research Center

Gregory M. Laird

Accelevir Diagnostics

Kristen D. Ritter

Accelevir Diagnostics

Jayesh Shah

Columbia University

Asim K. Debnath

New York Blood Center

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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 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.

Suggested Citation

Chang, Lin-Chun and Yin, Michael and Laird, Gregory M. and Ritter, Kristen D. and Shah, Jayesh and Debnath, Asim K. and Administrator, Sneak Peek, A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates ex xivo Reservoirs from Patients. Available at SSRN: https://ssrn.com/abstract=5025047 or http://dx.doi.org/10.2139/ssrn.5025047
This version of the paper has not been formally peer reviewed.

Lin-Chun Chang (Contact Author)

New York Blood Center ( email )

United States

Michael Yin

Columbia University - Aaron Diamond AIDS Research Center ( email )

3022 Broadway
New York, NY 10027
United States

Gregory M. Laird

Accelevir Diagnostics ( email )

Kristen D. Ritter

Accelevir Diagnostics ( email )

Baltimore
United States

Jayesh Shah

Columbia University ( email )

Asim K. Debnath

New York Blood Center ( email )

United States

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