Reactivation of Latent HIV-1 by Inhibition of BRD4

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, w...

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Main Authors:	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
Format:	Article
Language:	English
Published:	Elsevier 2012-10-01
Series:	Cell Reports
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211124712002896

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spelling	doaj-c79ff68d377844489f7b58a07affe3be2020-11-24T21:46:48ZengElsevierCell Reports2211-12472012-10-012480781610.1016/j.celrep.2012.09.008Reactivation of Latent HIV-1 by Inhibition of BRD4Jian Zhu0Gaurav D. Gaiha1Sinu P. John2Thomas Pertel3Christopher R. Chin4Geng Gao5Hongjing Qu6Bruce D. Walker7Stephen J. Elledge8Abraham L. Brass9Department of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USADepartment of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USADepartment of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USADepartment of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02127, USARagon Institute of Massachusetts General Hospital, MIT and Harvard University, Charlestown, MA 02129, USA 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. http://www.sciencedirect.com/science/article/pii/S2211124712002896
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	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
spellingShingle	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 Reactivation of Latent HIV-1 by Inhibition of BRD4 Cell Reports
author_facet	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
author_sort	Jian Zhu
title	Reactivation of Latent HIV-1 by Inhibition of BRD4
title_short	Reactivation of Latent HIV-1 by Inhibition of BRD4
title_full	Reactivation of Latent HIV-1 by Inhibition of BRD4
title_fullStr	Reactivation of Latent HIV-1 by Inhibition of BRD4
title_full_unstemmed	Reactivation of Latent HIV-1 by Inhibition of BRD4
title_sort	reactivation of latent hiv-1 by inhibition of brd4
publisher	Elsevier
series	Cell Reports
issn	2211-1247
publishDate	2012-10-01
description	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.
url	http://www.sciencedirect.com/science/article/pii/S2211124712002896
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Reactivation of Latent HIV-1 by Inhibition of BRD4

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