A Pioneer Transcription Factor and Type I Nuclear Hormone Receptors Synergistically Activate the Bovine Herpesvirus 1 Infected Cell Protein 0 (ICP0) Early Promoter.

Following bovine herpesvirus 1 (BoHV-1) acute infection of ocular, oral, or nasal cavities, sensory neurons within trigeminal ganglia are an important site for latency. Stress, as mimicked by the synthetic corticosteroid dexamethasone, consistently induces reactivation from latency. Expression of two key viral transcriptional regulatory proteins, BoHV-1 infected cell protein 0 (bICP0) and bICP4, are regulated by sequences within the immediate early promoter (IEtu1). A separate early promoter also drives bICP0 expression, presumably to ensure sufficient levels of this important transcriptional regulatory protein. Productive infection and bICP0 early promoter activity are cooperatively transactivated by Krüppel-like factor 4 (KLF4) and a type I nuclear hormone receptor (NHR), androgen receptor, glucocorticoid receptor, or progesterone receptor. The bICP0 early promoter contains three separate transcriptional enhancers that mediate cooperative transactivation. In contrast to the IEtu1 promoter, the bICP0 early promoter lacks consensus type I NHR binding sites. Consequently, we hypothesized that KLF4 and Sp1 binding sites are essential for type I NHR and KLF4 to transactivate the bICP0 promoter. Mutating KLF4 and Sp1 binding sites in each enhancer domain significantly reduced transactivation by KLF4 and a type I NHR. Chromatin immunoprecipitation (ChIP) studies demonstrated that occupancy of bICP0 early promoter sequences by KLF4 and type I NHR is significantly reduced when KLF4 and/or Sp1 binding sites are mutated. These studies suggest that cooperative transactivation of the bICP0 E promoter by type I NHRs and a stress-induced pioneer transcription factor (KLF4) promote viral replication and spread in neurons or nonneural cells in reproductive tissue.