Cell Reports 2012-10-25

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

Index: Cell Rep. 2(4) , 807-16, (2012)

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Abstract

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.Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.