{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T19:13:59Z","timestamp":1780600439526,"version":"3.54.1"},"reference-count":81,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["2R56AI104416-11A1"],"award-info":[{"award-number":["2R56AI104416-11A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. The \u201cshock and kill\u201d 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.<\/jats:p>","DOI":"10.3390\/ijms26062772","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T09:18:26Z","timestamp":1742375906000},"page":"2772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A First-in-Class Dual Degrader of Bcl-2\/Bcl-xL Reverses HIV Latency and Minimizes Ex Vivo Reservoirs from Patients"],"prefix":"10.3390","volume":"26","author":[{"given":"Lin-Chun","family":"Chang","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9346-9056","authenticated-orcid":false,"given":"Michael T.","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Laird","sequence":"additional","affiliation":[{"name":"Accelevir Diagnostics, Baltimore, MD 21202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen D.","family":"Ritter","sequence":"additional","affiliation":[{"name":"Accelevir Diagnostics, Baltimore, MD 21202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayesh G.","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2761-0506","authenticated-orcid":false,"given":"Asim K.","family":"Debnath","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/387183a0","article-title":"Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection","volume":"387","author":"Chun","year":"1997","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/nm1295-1284","article-title":"In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency","volume":"1","author":"Chun","year":"1995","journal-title":"Nat. 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