BRD4 modulator ZL0580 and LEDGINs additively block and lock HIV-1 transcription

Eline Pellaers, Julie Janssens, Lore Wils, Alexe Denis, Anayat Bhat, Siska Belle, Da Feng, Frauke Christ, Peng Zhan and Zeger Debyser ()
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Eline Pellaers: Herestraat 49
Julie Janssens: University of California San Francisco (UCSF)
Lore Wils: Herestraat 49
Alexe Denis: Herestraat 49
Anayat Bhat: Washington University (WashU)
Siska Belle: Herestraat 49
Da Feng: Shandong University
Frauke Christ: Herestraat 49
Peng Zhan: Shandong University
Zeger Debyser: Herestraat 49

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59398-7

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