Reactivation of Latent HIV-1 by Inhibition of BRD4

SummaryHIV-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.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► 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