Transcriptional consequences of herpes simplex virus 1 ICP4 inducible expression in uninfected cells

Successful viral infections reflect the balanced outcome of a tightly regulated program of viral gene expression and manipulation of the host cell to favor production of new infectious particles. The productive replication cycle of herpes simplex virus 1 (HSV-1) is dependent on the immediate-early essential transcription factor ICP4, which positively or negatively regulates transcription of immediate-early, early, and late HSV-1 genes at different steps in the temporal cascade, largely through sequence-specific binding to cis-acting regulatory elements. In contrast, direct regulation of host transcription programming by ICP4 is less well understood. In this study we exogenously expressed doxycycline-inducible wild-type and mutant ICP4 proteins in uninfected primary human fibroblasts and performed RNA-Seq to identify ICP4-driven changes to the host transcriptome. Cross-referencing our findings to a published dataset of ICP4-dependent changes to the host transcriptome in cells infected with HSV-1 provided validation for a subset of ICP4-regulated differentially-expressed genes. Furthermore, mutations in ICP4 that disrupt interactions with the host transcriptional machinery or interfere with site-specific DNA binding further modified this ICP4-driven remodeling of host transcription programming. Taken together, these data provide a comprehensive transcriptomic analysis of ICP4-driven dysregulation of host gene expression in uninfected cells.