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

Daniela Boehm, Vincenzo Calvanese, Roy David 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 journalArticle

Abstract

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
Volume12
Issue number3
DOIs
StatePublished - Feb 1 2013
Externally publishedYes

Fingerprint

HIV
tat Gene Products
Virus Integration
Peptide Elongation Factors
Proteins
Jurkat Cells
Viral Proteins
Hematologic Neoplasms
Fluorescence Microscopy
Small Interfering RNA
HIV Infections
Transcription Factors
Inflammation
T-Lymphocytes
Therapeutics
Population

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Boehm, D., Calvanese, V., Dar, R. D., Xing, S., Schroeder, S., Martins, L., ... Ott, M. (2013). BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle, 12(3), 452-462. https://doi.org/10.4161/cc.23309

BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. / Boehm, Daniela; Calvanese, Vincenzo; Dar, Roy David; Xing, Sifei; Schroeder, Sebastian; Martins, Laura; Aull, Katherine; Li, Pao Chen; Planelles, Vicente; Bradner, James E.; Zhou, Ming Ming; Siliciano, Robert F.; Weinberger, Leor; Verdin, Eric; Ott, Melanie.

In: Cell Cycle, Vol. 12, No. 3, 01.02.2013, p. 452-462.

Research output: Contribution to journalArticle

Boehm, D, Calvanese, V, Dar, RD, Xing, S, Schroeder, S, Martins, L, Aull, K, Li, PC, Planelles, V, Bradner, JE, Zhou, MM, Siliciano, RF, Weinberger, L, Verdin, E & Ott, M 2013, 'BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism', Cell Cycle, vol. 12, no. 3, pp. 452-462. https://doi.org/10.4161/cc.23309
Boehm, Daniela ; Calvanese, Vincenzo ; Dar, Roy David ; Xing, Sifei ; Schroeder, Sebastian ; Martins, Laura ; Aull, Katherine ; Li, Pao Chen ; Planelles, Vicente ; Bradner, James E. ; Zhou, Ming Ming ; Siliciano, Robert F. ; Weinberger, Leor ; Verdin, Eric ; Ott, Melanie. / BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. In: Cell Cycle. 2013 ; Vol. 12, No. 3. pp. 452-462.
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AU - Li, Pao Chen

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