CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

Horvath, R.; Brumme, Z. L.; Sadowski, I.

doi:10.1101/2023.06.07.544021

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bioRxiv · 10.1101/2023.06.07.544021

CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells

Horvath, R.·Brumme, Z. L.·Sadowski, I.

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Abstract

Latent HIV-1 provirus represents a barrier towards a cure for infection, but is dependent upon the host RNA Pol II machinery for expression. We find that inhibitors of the RNA Pol II mediator kinases CDK8/19, Senexin A and BRD6989, inhibit induction of HIV-1 expression in response to latency reversing agents and T cell signaling agonists. These inhibitors were found to impair recruitment of RNA Pol II to HIV-1 LTR. HIV-1 expression in response to several latency reversal agents was impaired upon disruption of CDK8 by shRNA or gene knockout. However, the effects of CDK8 depletion did not entirely mimic CDK8/19 kinase inhibition suggesting that the mediator kinases are not functionally redundant. Furthermore, treatment of CD4+ PBMCs isolated from people living with HIV-1 and who are receiving ART with Senexin A inhibited induction of virus replication in response to T cell stimulation by PMA and ionomycin. These observations indicate that the mediator kinases CDK8 and CDK19, play a significant role for regulation of HIV-1 transcription, and that small molecule inhibitors of these enzymes may contribute to therapies designed to promote deep latency involving the durable suppression of provirus expression.

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Horvath, R., Brumme, Z. L., Sadowski, I.. 2023-06-07. CDK8 inhibitors antagonize HIV-1 reactivation and promote provirus latency in T cells. https://doi.org/10.1101/2023.06.07.544021

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