Herpes Simplex viral nucleoprotein creates a competitive transcriptional environment facilitating robust viral transcription and host shut off

Summary Herpes simplex virus-1 (HSV-1) replicates within the nucleus coopting the host’s RNA Polymerase II (Pol II) machinery for production of viral mRNAs culminating in host transcriptional shut off. The mechanism behind this rapid reprogramming of the host transcriptional environment is largely unknown. We identified ICP4 as responsible for preferential recruitment of the Pol II machinery to the viral genome. ICP4 is a viral nucleoprotein which binds double stranded DNA. We determined ICP4 discriminately binds the viral genome due to the absence of cellular nucleosomes and high density of cognate binding sites. We posit that ICP4’s ability to recruit not just Pol II, but also more limiting essential components, such as TBP and Mediator create a competitive transcriptional environment. These distinguishing characteristics ultimately result in a rapid and efficient reprogramming of the host’s transcriptional machinery, which does not occur in the absence of ICP4. Highlights HSV-1 ICP4 coats the viral genome promoting robust recruitment of Pol II transcription machinery. ICP4 prefers the viral genome due to the absence of nucleosomes and density of binding motifs. At high concentrations ICP4 promiscuously binds DNA including euchromatic host promoters. ICP4 is required for host transcriptional shut off, independent of genome replication.