HIV cure strategies that aim to induce viral reactivation for immune clearance leverage latency reversal agents to modulate host pathways, which directly or indirectly facilitate viral reactivation. Inhibition of BET (bromo and extra-terminal domain) family member BRD4 reverses HIV latency, but enthusiasm for the use of BET inhibitors in HIV cure studies is tempered by concerns over inhibition of other BET family members and dose-limiting toxicities in oncology trials.
A group of researchers evaluated the potential for bivalent chemical degraders targeted to the BET family as alternative latency reversal agents. They observed that despite highly potent and selective BRD4 degradation in primary CD4+ T-cells from ART-suppressed donors, BRD4 degraders failed to induce latency reversal as compared to BET inhibitors. This activity is dependent on the shift of BRD4 from chromatin-bound to soluble, and retargeting of P-TEFb to chromatin, which is dependent on intact BRD4 but independent of the bromodomains.
Anne-Marie Turner, PhD, Jennifer Kirchherr, PhD, Nancie M. Archin, PhD, Lindsey James, PhD, and David Margolis, MD contributed to this research.