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

Authors

Ngassaki Yoka, C. D., Goulet, J.-P., Khalfi, S., Chatterjee, D., Wiche Salinas, T. R., Zhang, Y., Raymond Marchand, L., Moreaux, J., Dias, J., Fert, A., Chomont, N., Richard, J., Finzi, A., Cermakian, N., Bell, B., Routy, J.-P., Solt, L., Ancuta, P.

Abstract

The circadian clock repressors REV-ERB/{beta} control rhythmic gene expression and inhibit HIV-1 transcription. Whether REV-ERB/{beta} modulate the HIV-1 replication cycle beyond transcription remains unknown. Here, we demonstrate that memory CD4+ T-cells predominantly express the REV-ERB{beta} isoform ex vivo and that T-cell receptor (TCR) triggering downregulates both REV-ERB/{beta} expression, with levels of REV-ERB/{beta} 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-ERB/{beta} 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-ERB/{beta} targets. Thus, pharmacological inhibition of REV-ERB/{beta} uniquely combines a latency reversal activity with the inhibition of progeny virion spread.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 25 Aug 2026.

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