Stimulation of bovine herpesvirus-1 productive infection by the adenovirus E1A gene and a cell cycle regulatory gene, E2F-4

Identifying cellular genes that promote bovine herpesvirus-1 (BHV-1) productive infection is important, as BHV-1 is a significant bovine pathogen. Previous studies demonstrated that BHV-1 DNA is not very infectious unless cotransfected with a plasmid expressing blCP0, a viral protein that stimulates expression of all classes of viral promoters. Based on these and other studies, we hypothesize that the ability of blCP0 to interact with and modify the function of cellular proteins stimulates virus transcription. If this prediction is correct, cellular proteins that activate virus transcription could, in part, substitute for blCP0 functions. The adenovirus Ell A gene and blCP0 encode proteins that are potent activators of viral gene expression, they do not specifically bind DNA and both proteins interact with chromatin-remodel ling enzymes. Because of these functional similarities, Ell A was tested initially to see if it could stimulate BHV-1 productive infection. Ell A consistently stimulates BHV-1 productive infection, but not as efficiently as blCP0. The ability of E1A to bind Rb family members plays a role in stimulating productive infection, suggesting that E2F family members activate productive infection. E2F-4, but not E2F-1, E2F-2 or E2F-5, activates productive infection with similar efficiency as Ell A. Next, E2F family members were examined for their ability to activate the BHV-1 immediate-early (IE) transcription unit 1 (IEtu1) promoter, as it regulates IE expression of blCP0 and blCP4. E2F-1 and E2F-2 strongly activate the IEtu1 promoter, but not a BHV-1 IEtu2 promoter or a herpes simplex virus type 1 ICPO promoter construct. These studies suggest that E2F family members can stimulate BHV-1 productive infection.