BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism

D Boehm, V Calvanese, RD Dar, S Xing, S Schroeder… - Cell cycle, 2013 - Taylor & Francis
D Boehm, V Calvanese, RD Dar, S Xing, S Schroeder, L Martins, K Aull, PC Li, V Planelles
Cell cycle, 2013Taylor & Francis
The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal
(BET) proteins has recently emerged in hematological malignancies and chronic
inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417)
reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing
latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we
show that this activation is dependent on the positive transcription elongation factor p-TEFb …
The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal (BET) proteins has recently emerged in hematological malignancies and chronic inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417) reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we show that this activation is dependent on the positive transcription elongation factor p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action. Instead, we find that the related BET protein, BRD2, enforces HIV latency in the absence of Tat, pointing to a new target for BET inhibitor treatment in HIV infection. In shRNA-mediated knockdown experiments, knockdown of BRD2 activates HIV transcription to the same extent as JQ1 treatment, while a lesser effect is observed with BRD4. In single-cell time-lapse fluorescence microscopy, quantitative analyses across ~2,000 viral integration sites confirm the Tat-independent effect of JQ1 and point to positive effects of JQ1 on transcription elongation, while delaying re-initiation of the polymerase complex at the viral promoter. Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency.
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