A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs DOI Open Access
L.‐H. Chang, Michael T. Yin, Gregory M. Laird

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

ABSTRACT The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) selectively inducing cell death infected cells. However, current LRAs have shown limited efficacy eliminating the ex vivo HIV reservoir. We repurposed PZ703b, pro-apoptotic protein degrader initially developed for anti-leukemia therapy, target eradication. PZ703b induced degradation Bcl-2 Bcl-xL, activating non-canonical NF-kB pathway caspases cascade, resulting reversal selective apoptosis Treatment from ART-suppressed patients achieved ∼50% reduction replication-competent Our study provides proof-of-concept using degraders reverse induce death, highlighting PZ703b’s potential cure strategies. This approach may pave way novel therapeutic interventions aimed at HIV-inducible

Language: Английский

A First-in-Class Dual Degrader of Bcl-2/Bcl-xL Reverses HIV Latency and Eliminates Ex Vivo Reservoirs DOI Open Access
L.‐H. Chang, Michael T. Yin, Gregory M. Laird

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

ABSTRACT The persistence of latent HIV-1 proviruses in CD4+ T cells is a major obstacle to curing HIV. “shock and kill” strategy involves reversing latency with latency-reversing agents (LRAs) selectively inducing cell death infected cells. However, current LRAs have shown limited efficacy eliminating the ex vivo HIV reservoir. We repurposed PZ703b, pro-apoptotic protein degrader initially developed for anti-leukemia therapy, target eradication. PZ703b induced degradation Bcl-2 Bcl-xL, activating non-canonical NF-kB pathway caspases cascade, resulting reversal selective apoptosis Treatment from ART-suppressed patients achieved ∼50% reduction replication-competent Our study provides proof-of-concept using degraders reverse induce death, highlighting PZ703b’s potential cure strategies. This approach may pave way novel therapeutic interventions aimed at HIV-inducible

Language: Английский

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