Targeting CDK12/CYCLIN K induces HIV gene activation and latency reversal which is mediated by P-TEFb

Abstract

The administration of antiretroviral therapy has successfully suppressed the replication of Human immunodeficiency virus and substantially inhibited viral infection. However, HIV still persists in long-lived infected cell reservoirs that are resistant to therapy and to immune clearance, therefore a barrier for elimination of infection. HIV gene expression is tightly regulated by the cellular transcription machinery, where low levels of host and viral transcription factors and epigenetic constrains maintain viral persistence. Here, we show that selective targeting of CDK12/CYCLIN K (CCNK) induces both HIV-specific and a global gene activation program, which is mediated by positive transcription elongation factor b (P-TEFb). Targeting CDK12/CCNK triggers a robust HIV gene expression, accompanied with latency reversal and synergistic reactivation when combined with latency-reversing agents. Mechanistically, CDK12/CCNK inhibition promotes the recruitment of RNA Polymerase II and CDK9 to the viral promoter, accompanied with elevated levels of histone activation makers. Targeting CDK12/ CCNK also exerts a global gene activation program, by releasing P-TEFb from 7SK snRNP, and reshaping the chromatin landscape at promoter-proximal loci and gene bodies. Together, these results uncover a previously unrecognized compensatory interplay between transcriptional kinases that rewires the cellular gene expression program with implications for HIV latency reversal. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org