REV-ERBα/β Targeting Transcriptionally Reprograms HIV-Infected CD4 + T-Cells for Increased Viral Reactivation but Limited Virion Spread

Résumé fourni par la source

SUMMARY The circadian clock repressors REV-ERBα/β control rhythmic gene expression and inhibit HIV-1 transcription. Whether REV-ERBα/β modulate the HIV-1 replication cycle beyond transcription remains unknown. Here, we demonstrate that memory CD4 + T-cells predominantly express the REV-ERBβ isoform ex vivo and that T-cell receptor (TCR) triggering downregulates both REV-ERBα/β expression, with levels of REV-ERBα/β mRNA being lower in ART-treated people with HIV (PWH) receiving antiretroviral therapy (ART) compared to people without HIV (PWoH) before/after TCR triggering. In single-round infection, the REV-ERBα/β antagonist SR8278 facilitated HIV-1 reverse transcription, integration, and intracellular HIV-p24 expression, but limited virion release. Moreover, SR8278 downregulated CCR5 mRNA expression, inhibited R5-tropic HIV-1 replication in vitro, and limited viral outgrowth in CD4 + T-cells from ART-treated PWH. Finally, genome-wide RNA-sequencing and functional validations revealed HIV-1 restriction/dependency factors that represent novel putative REV-ERBα/β targets. Thus, pharmacological inhibition of REV-ERBα/β uniquely combines a latency reversal activity with the inhibition of progeny virion spread. Abstract Figure Graphical Abstract

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.