Inhibition of CDK12/CDK13-CYCLIN K rewires P-TEFb signaling to reverse HIV-1 latency and modulate cellular gene expression.

Persistent HIV-1 latency in long-lived CD4⁺ T-cell reservoirs remains a major obstacle towards viral eradication. Current antiretroviral therapy (cART) exhibits limited clinical efficacy, highlighting the need for new therapeutic interventions. Here, we identify the CDK12/CDK13-Cyclin K (CCNK) complex as a regulator of HIV-1 latency. Pharmacological inhibition of CDK12/CDK13-CCNK with the SR-4835 inhibitor robustly reversed HIV-1 latency in the absence of additional stimuli, both in T cell models and in primary CD4⁺ T cells from people living with HIV-1 receiving cART. Targeting of CDK12/CDK13-CCNK with SR-4835 further synergized HIV-1 latency reversal and enhanced viral reactivation when co-treated with established Latency Reversal Agents. Mechanistically, CDK12/CDK13-CCNK inhibition promoted the release of P-TEFb (CDK9/CYCLIN T) from its inhibitory 7SK snRNP complex, resulting in increased recruitment of RNA polymerase II, CDK9 activation, and remodeled chromatin that overall drove productive HIV-1 transcription. Beyond HIV-1 reactivation, our findings reveal a previously unrecognized compensatory interplay between transcriptional kinases that activate gene expression, thereby rewiring cellular transcriptional programs. Together, this study identifies CDK12/CDK13-CCNK complex as a therapeutic target for HIV-1 latency reversal and provides a mechanistic rationale for improving strategies aimed at achieving an HIV cure.