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BRD4 modulator ZL0580 and LEDGINs additively block and lock HIV-1 transcription
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BRD4 modulator ZL0580 and LEDGINs additively block and lock HIV-1 transcription
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Journal Article
BRD4 modulator ZL0580 and LEDGINs additively block and lock HIV-1 transcription
2025
Overview
The persistence of HIV-1 in a latent state within long-lived immune cells remains a major barrier to a cure for HIV-1 infection. The “block-and-lock” strategy aims to silence the HIV-1 provirus permanently using latency promoting agents (LPAs). LEDGINs, a well-known class of LPAs, inhibit the interaction between viral integrase and LEDGF/p75, reducing viral integration and retargeting the provirus to regions resistant to reactivation. However, proximity to enhancers may still permit residual transcription. Given BRD4’s central role in the enhancer biology, we now test two BRD4 modulators, JQ1 and ZL0580. Mechanistic studies reveal that JQ1 and ZL0580 have contrasting effects on Tat-dependent HIV-1 transcription, resulting in JQ1 promoting viral reactivation and ZL0580 inducing transcriptional silencing. Combining ZL0580 with LEDGINs has an additive effect in blocking HIV-1 transcription and reactivation, in both cell lines and primary cells. These findings demonstrate the potential of ZL0580 to enhance the block-and-lock cure strategy.
In this work, we combine LEDGINs with BRD4 modulator ZL0580 to achieve a functional HIV cure. This approach silences the virus by retargeting viral integration into silent chromatin and blocking enhancers, offering a powerful combination strategy to block-and-lock HIV.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 14/32
/ 14/63
/ 49
/ 49/1
/ 49/109
/ 49/31
/ 49/39
/ Blocking
/ Bromodomain Containing Proteins
/ Cell Cycle Proteins - metabolism
/ HIV
/ HIV Infections - drug therapy
/ Human immunodeficiency virus
/ Humanities and Social Sciences
/ Humans
/ Latency
/ Proteins
/ Science
/ Toxicity
/ Transcription Factors - antagonists & inhibitors
/ Transcription Factors - genetics
/ Transcription Factors - metabolism
/ Transcription, Genetic - drug effects
/ Virus Activation - drug effects
/ Virus Integration - drug effects
/ Virus Latency - drug effects
/ Viruses
