Cell Reports
Volume 2, Issue 4, 25 October 2012, Pages 807-816
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Report
Reactivation of Latent HIV-1 by Inhibition of BRD4

https://doi.org/10.1016/j.celrep.2012.09.008Get rights and content
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Summary

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.

Highlights

► BRD4 depletion or inhibition with JQ1 increases HIV-1 replication and gene expression ► BRD4 inhibition increases Tat-dependent transcriptional elongation and Tat–PTEF-b association ► BRD4 inhibition alleviates HIV-1 latency in cell-line models ► JQ1 with HDF activators enhances HIV-1 replication in primary and latently infected T cells

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Present address: Microbiology and Physiological Systems (MaPS) Department, University of Massachusetts Medical School, Worcester, MA 01655, USA