Inhibition of bovine herpesvirus-4 replication by arsenite through downregulation of the extracellular signal-regulated kinase signaling pathway.

Infection of bovine arterial endothelial (BAE) cells with bovine herpesvirus-4 (BHV-4) induced biphasic activation of one of the cellular mitogen-activated protein kinase (MAPK) downstream targets, extracellular signal-regulated kinase (ERK). ERK activity reached a maximum within 0.5 h postinfection (h.p.i.), and had declined and returned to basal levels by 2 h.p.i. However, at 18–24 h.p.i., a second phase of increased ERK activation occurred. Treatment of BHV-4-infected BAE cells with either U0126, a potent inhibitor of MAPK/ERK kinase, or arsenite dose-dependently blocked ERK activation and inhibited viral DNA synthesis and viral replication in the culture. Further detailed investigations revealed that transcription of viral immediate-early gene 2 (IE-2), which is required for viral DNA replication, was significantly suppressed by both U0126 and arsenite. These results imply that ERK activation may play a pivotal role in herpesvirus replication, and that inhibition of ERK activation can effectively inhibit viral IE protein synthesis and viral replication.