Regulation of Alpha-herpesvirus Reactivation from Latency by Stress

Bovine herpesvirus 1 (BHV-1) establishes a lifelong latent infection in sensory neurons following acute infection. Increased corticosteroid levels, due to stress, increases the incidence of reactivation from latency. Within minutes, corticosteroids activate the glucocorticoid receptor and transcription of promoters containing a glucocorticoid receptor element. The synthetic corticosteroid dexamethasone consistently induces reactivation from latency. Cellular transcription factors are induced by dexamethasone in trigeminal ganglionic neurons within 1.5 h after dexamethasone treatment, suggesting they promote viral gene expression during the early phases of reactivation from latency, which we operationally defined as the escape from latency. Within 90 min after latently infected calves are treated with dexamethasone, two BHV-1 regulatory proteins, BHV-1infected cell protein 0 (bICP0) and viral protein 16 (VP16), are expressed in the same neuron. Two other late proteins, glycoprotein C and D, were not detected until 6 h after dexamethasone treatment and were detected in only a few neurons. These studies provide evidence that VP16 and the promiscuous viral trans-activator (bICP0) are expressed during the escape from latency, suggesting they promote the production of infectious virus in a small subset of latently infected neurons. We now provide evidence that neurons expressing the glucocorticoid receptor expressed bICP0 or VP16 at 1.5 h after dexamethasone treatment. VP16 and bICP0 can also be detected at 22 and 33 min after dexamethasone (DEX) treatment of latently infected calves. However, we were unable to discern whether VP16 or bICP0 was expressed at early times after reactivation. VP16+ neurons consistently express the glucocorticoid receptor suggesting corticosteroidmediated activation of its receptor rapidly stimulates reactivation from latency.