Bovine herpesvirus 1 (BoHV-1) is an important pathogen of cattle and cofactor for bovine respiratory disease, a polymicrobial disease. Acute infection of cattle leads to abundant expression of lytic cycle viral genes, high levels of virus shedding, and clinical symptoms. Following acute infection, lifelong latency is established in sensory neurons. Only the latency-related (LR) gene locus, which encodes at least two micro-RNAs and several proteins, is abundantly expressed in latently infected neurons. Increased corticosteroids, due to external stressors, disrupt the maintenance of latency and increase the incidence of reactivation from latency, which is crucial for virus transmission. For example, calves latently infected with BoHV-1 consistently reactivate from latency following a single intravenous (IV) injection of the synthetic corticosteroid dexamethasone. In contrast to wild-type BoHV-1, an LR-mutant virus that has three in-frame stop codons at the amino terminus of the first open reading frame in the LR gene (ORF2) does not reactivate from latency following dexamethasone treatment. The ability of dexamethasone to initiate BoHV-1 reactivation from latency in calves makes it an attractive model to identify early events that occur during reactivation from latency. Viral and cellular factors that regulate the BoHV-1 latency-reactivation cycle are discussed in this review.
Part of the book: Herpesviridae
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 finger. Furthermore, the glucocorticoid receptor (GR) is consistently detected in TG neurons 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.
Part of the book: Transcriptional and Post-transcriptional Regulation