BET degraders reveal BRD4 disruption of 7SK and P-TEFb is critical for effective reactivation of latent HIV in CD4+ T-cells

Multiple factors and pathways contribute to the maintenance of HIV latency, including bromo and extra-terminal domain (BET) family member BRD4. While small molecule inhibitors of the BET family result in latency reversal, enthusiasm for the use of BET inhibitors in HIV cure is limited due to toxicity concerns. We examined BRD4-selective chemical degraders as alternatives to BET inhibitors but found two robust degraders failed to induce latency reversal. We observed key differences in the ability of BET inhibitors versus BET degraders to disrupt P-TEFb, a key cellular activator of transcription and a complex required for HIV reactivation. We present a new model for the role of BRD4 in HIV latency and propose that BRD4 be reconsidered as an activator rather than a repressor of HIV transcription in the context of HIV cure strategies.