Small molecule inhibitors of transcriptional cyclin-dependent kinases impose HIV-1 latency, presenting “block and lock” treatment strategies

Abstract

Current antiretroviral therapy for HIV-1 infection does not represent a cure for infection as viral rebound inevitably occurs following discontinuation of treatment. The “block and lock” therapeutic strategy is intended to enforce proviral latency and durably suppress viremic reemergence in the absence of other intervention. The transcription-associated cyclin-dependent protein kinases (tCDKs) are required for expression from the 5´ HIV-1 long-terminal repeat, but the therapeutic potential of inhibiting these kinases for enforcing HIV-1 latency has not been characterized. Here, we expanded previous observations to directly compare the effect of highly selective small molecule inhibitors of CDK7 (YKL-5-124), CDK9 (LDC000067), and CDK8/19 (Senexin A), and found each of these prevented HIV-1 provirus expression at concentrations that did not cause cell toxicity. Inhibition of CDK7 caused cell cycle arrest, whereas CDK9 and CDK8/19 inhibitors did not, and could be continuously administered to establish proviral latency. Upon discontinuation of drug administration, HIV immediately rebounded in cells that had been treated with the CDK9 inhibitor, while proviral latency persisted for several days in cells that had been treated with CDK8/19 inhibitors. These results identify the mediator kinases CDK8/CDK19 as potential “block and lock” targets for therapeutic suppression of HIV-1 provirus expression.

Targeting Viral Transcription for HIV Cure Strategies

“…This is also the case of inhibitors of thioredoxin reductase, a protein involved in maintaining redox balance in host cells, which were discovered by screening for gene expression noise, and they promote HIV-1 latency in vitro [7]. Senexin A is an inhibitor of the cyclin-dependent protein kinases CDK8/CDK19, which are required for expression from 5 ′ HIV-1 LTR, and suppresses proviral reactivation in vitro [84].…”