Pioneer transcription factors, progesterone receptor and Krüppel like transcription factor 4, cooperatively stimulate the bovine herpesvirus 1 ICP0 early promoter and productive late protein expression

Bovine herpesvirus 1 (BoHV-1), including commercially available modified live vaccines, readily infect the fetus and ovaries, which can cause reproductive failure. The BoHV-1 latency-reactivation cycle in sensory neurons further complicates reproductive failure because progesterone sporadically induces reactivation from latency. The progesterone receptor (PR) and Krüppel-like transcription factor 15 (KLF15) cooperatively stimulate productive infection and the immediate early transcription unit 1 (IEtu1) promoter. In addition to the IEtu1 promoter, the bICP0 gene also contains a separate early (E) promoter. In this study, we tested the hypothesis that PR and KLF family members transactivate the bICP0 E promoter. PR and KLF4 stimulated bICP0 E promoter activity and expression of late productive viral protein expression in a cooperative manner. Additional studies revealed three enhancer domains within the bICP0 E promoter were responsive to PR and KLF4. Chromatin immunoprecipitation studies demonstrated PR and KLF4 occupy bICP0 E promoter sequences in transfected Neuro-2A cells and at late times following infection of bovine kidney cells. Co-immunoprecipitation studies indicated PR and KLF4 stably interact with each other. These studies suggest cooperative activation of the bICP0 E promoter by PR and KLF4 correlate with interactions between these pioneer transcription factors.