An Epigenetic Compound Library Screen Identifies BET Inhibitors That Promote HSV-1 and -2 Replication by Bridging P-TEFb to Viral Gene Promoters through BRD4

The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic Infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV Infection. We show that treatment with pan BD domain inhibitor enhanced both HSV Infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 Inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV Infection. BRD4 regulates HSV replication through complex formation involving CDK9 and RNAP II; whereas, JQ1 promotes HSV-1 Infection by allocating the complex to HSV gene promoters. Therefore, suppression of BRD4 expression or inhibition of CDK9 activity impeded HSV Infection. Our data support a model that JQ1 enhances HSV Infection by switching BRD4 to transcription regulation of viral gene expression from chromatin targeting since transient expression of BRD4 BD1 or BD1/2 domain had similar effect to that by JQ1 treatment. In addition to the identification that BRD4 is a modulator for JQ1 action on HSV Infection, this study demonstrates BRD4 has an essential role in HSV Infection.