Replication‐dependent expression of Herpes simplex virus late genes is controlled by P‐TEFb/CDK9 and DSIF/SPT5

Abstract

Herpes simplex virus expresses three classes of genes: immediate early, early and late genes. The immediate early genes are induced by VP16, whereas early and late genes depend on the sequence‐independent transcription factor ICP4. In addition expression of late genes is dependent on on‐going DNA synthesis. Here we demonstrate that late gene expression, e.g. glycoprotein C and the capsid protein UL38, is specifically inhibited by the P‐TEFb/CDK9 inhibitor DRB. In contrast, expression of early genes, e.g. ICP8 and UL39, is not affected by DRB. Furthermore, DNA replication proceeds normally in DRB‐treated virus‐infected cells. Knock‐down of DSIF, a target of P‐TEFb/CDK9, severely reduces expression of late genes but do not affect synthesis of DNA. ChIP experiments demonstrate that transcription complexes are efficiently assembled on the UL38 late gene already at 3 hrs, well before transcription starts. At 6 hrs p.i., when synthesis of DNA has started, a major redistribution of transcription complexes occurs. However, in DRB‐treated cells no such redistribution is seen. Our observations are compatible with a model in which DNA replication promotes the recruitment of P‐TEFb/CDK9 to virus DNA and acts continuously on late genes during the later phase of virus replication.