The Glucocorticoid Receptor and Certain KRÜPPEL-Like Transcription Factors have the Potential to Synergistically Stimulate Bovine Herpesvirus 1 Transcription and Reactivation from Latency

Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes life-long latency in sensory neurons within trigeminal ganglia (TG). Stress, as mimicked by the synthetic corticosteroid dexamethasone, consistently induces reactivation in calves latently infected with BoHV-1. Dexamethasone induces expression of several transcription factors in TG neurons during early stages of reactivation, including Krüppel-like transcription factors (KLF): KLF4, KLF6, KLF15, and promyelocytic leukemia zinc fin -ger. Furthermore, the glucocorticoid receptor (GR) is consistently detected in TG neu- rons expressing viral regulatory proteins during reactivation from latency. The viral immediate early transcription unit 1 (IEtu1) promoter that drives expression of two viral transcription factors (bICP0 and bICP4) contains two GR response elements (GREs) and is stimulated by DEX. KLF15 and the GR form a feed forward transcription loop that synergistically stimulates productive infection and IEtu1 promoter activity. New studies demonstrate the GR and KLF6 synergistically stimulate productive infection and IEtu1 promoter activity if the GREs are intact. Furthermore, the GR and KLF6 interact with wild-type GREs within the IEtu1 promoter, but not GRE mutants. These studies suggest that certain KLF family members and the GR can convert a silent viral genome in latently infected neurons into an actively transcribing genome during reactivation from latency.