Reactivation of Latent HIV-1 by Inhibition of BRD4

Jian Zhu; Gaurav D. Gaiha; Sinu P. John; Thomas Pertel; Christopher R. Chin; Geng Gao; Hongjing Qu; Bruce D. Walker; Stephen J. Elledge; Abraham L. Brass

doi:10.1016/j.celrep.2012.09.008

Cell Reports (Oct 2012)

Reactivation of Latent HIV-1 by Inhibition of BRD4

Jian Zhu,
Gaurav D. Gaiha,
Sinu P. John,
Thomas Pertel,
Christopher R. Chin,
Geng Gao,
Hongjing Qu,
Bruce D. Walker,
Stephen J. Elledge,
Abraham L. Brass

Affiliations

Jian Zhu: Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USA
Gaurav D. Gaiha: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA
Sinu P. John: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA
Thomas Pertel: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA
Christopher R. Chin: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA
Geng Gao: Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USA
Hongjing Qu: Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USA
Bruce D. Walker: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA
Stephen J. Elledge: Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USA
Abraham L. Brass: Ragon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA

DOI: https://doi.org/10.1016/j.celrep.2012.09.008
Journal volume & issue: Vol. 2, no. 4
pp. 807 – 816

Abstract

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HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the reduction of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small molecule inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the in vitro reactivation of latent HIV-1 in primary T cells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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