A screen of chromatin-targeting compounds identifies TAF1 as a novel regulator of HIV latency.

UNLABELLED: Antiretroviral therapy suppresses HIV replication but fails to eliminate the virus due to the persistence of a transcriptionally silent reservoir, which remains the primary barrier to a cure. HIV latency is maintained through chromatin-mediated repression, making epigenetic regulators attractive therapeutic targets. To identify new modulators of latency, we screened a focused library of 84 chromatin-targeting small molecules. This screen identified BAY-299, a bromodomain inhibitor selective for TAF1 and BRD1, as a latency-modulating compound. BAY-299 reactivated HIV expression and enhanced the efficacy of established latency-reversing agents, including vorinostat, prostratin, and iBET-151, in cell line models. CRISPR/Cas9-mediated knockout experiments demonstrated that TAF1, but not BRD1, is essential for maintaining HIV latency and that TAF1 depletion selectively increases HIV transcription with minimal effects on host gene expression. Dual knockout of TAF1 and Tat revealed that reactivation of HIV in the absence of TAF1 is partially Tat-dependent. Cleavage Under Targets and Release Using Nuclease analysis further showed that TAF1 depletion increased histone acetylation at the viral promoter and across the HIV gene body, suggesting a chromatin-based mechanism. These findings identify TAF1 as a novel regulator of HIV latency and demonstrate the utility of targeted chemical screening to uncover therapeutic vulnerabilities within the latent reservoir.

IMPORTANCE

HIV remains incurable due to the persistence of a transcriptionally silent reservoir in infected cells that is not eliminated by antiretroviral therapy. This transcriptionally silent state, known as latency, is controlled by host cell factors that regulate access to the viral genome. In this study, we identified the host protein TAF1 as a key regulator that maintains HIV in a latent state in cell line models of latency. Using both genetic and chemical approaches, we demonstrate that reducing TAF1 levels selectively increases HIV gene expression without broadly disrupting host gene transcription. These findings highlight a previously unrecognized mechanism of HIV latency control and identify TAF1 as a potential therapeutic target for HIV. Understanding how host chromatin regulators contribute to latency is essential for developing strategies that aim to eliminate the persistent HIV reservoir.