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.

Ke Ren,Yayi Hou,Ren Xiang Tan,Xiaoqing Chen,Erguang Li,Yingyu Ma,Yue Dai,Yimei Fan,Wei Zhang,Robert F Kalejta

doi:10.1371/journal.ppat.1005950

Abstract

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.

Highlights

Herpes simplex virus-1 and -2 (HSV-1, HSV-2) are important pathogens of human diseases [1,2]
To investigate host factors involved in the lytic infection cycle, we screened a chemical library of epigenetic regulation and identified several bromodomain and extraterminal (BET) bromodomain inhibitors that enhanced both HSV-1
Using JQ1, a well-defined bromodomain-containing protein 4 (BRD4) inhibitor, as a model we showed that JQ1 increases HSV infection by allocating BRD4 to viral gene promoters

Summary

Introduction

Herpes simplex virus-1 and -2 (HSV-1, HSV-2) are important pathogens of human diseases [1,2]. HSV-1 infection is mainly associated with cold sores and blisters, while HSV-2 is a major factor of sexually transmitted infections [3,4]. Patients acquire HSV-1 at relatively young ages, while initial HSV-2 infections occur mainly after puberty, often transmitted after intimate contact [5]. HSV-1 and HSV-2 are double-stranded DNA viruses that are genetically similar and share many common features in infection and replication. The viruses are acquired initially by direct contact and replicate within mucosal epithelial cells. Latent infection serves as a reservoir of virus for recurrent infection and transmission to other individuals. Immeasurable advances have been made towards our understanding of HSV infection, the molecular machinery responsible for HSV replication regulation remains elusive and largely mystified

Methods

Results

Conclusion