Small molecule inhibitors of transcriptional Cyclin Dependent Kinases impose HIV-1 latency, presenting "block and lock" treatment strategies

Abstract

Antiretroviral therapy is not a cure for HIV-1 as viral rebound ensues immediately following discontinuation. The block and lock therapeutic strategy seeks to enforce proviral latency and durably suppress viremic reemergence in the absence of antiretroviral therapy. Transcriptional Cyclin Dependent Kinase activity regulates LTR transcription, however, the effect and therapeutic potential of inhibiting these kinases for enforcing HIV-1 latency remains unrecognized. Using newly developed small molecule inhibitors that are highly selective for either CDK7 (YKL-5-124), CDK9 (LDC000067), or CDK8/19 (Senexin A), we found that targeting any one of these kinases prevented HIV-1 expression at concentrations that showed no toxicity. Furthermore, although CDK7 inhibition induced cell cycle arrest, inhibition of CDK9 and/or CDK8/19 did not. Of particular interest, proviral latency as induced by CDK8/19 inhibition was maintained following drug removal while CDK9 inhibitor induced latency rebounded within 24 hrs of discontinuation. Our results indicate that the Mediator complex kinases, CDK8/CDK19, are attractive block and lock targets while sole disruption of P-TEFb is unlikely to be efficacious.