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

Daniela Boehm, Vincenzo Calvanese, Roy D. Dar, Sifei Xing, Sebastian Schroeder, Laura Martins, Katherine Aull, Pao Chen Li, Vicente Planelles, James E. Bradner, Ming Ming Zhou, Robert F. Siliciano, Leor Weinberger, Eric Verdin, Melanie Ott

Research output: Contribution to journalArticlepeer-review


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-TE Fb 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.

Original languageEnglish (US)
Pages (from-to)452-462
Number of pages11
JournalCell Cycle
Issue number3
StatePublished - Feb 1 2013
Externally publishedYes


  • BRD2
  • BRD4
  • HIV
  • I-BET
  • I-BET151
  • JQ1
  • Latency
  • MS417
  • P-TEFb
  • Tat

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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