Recurrent herpes simplex is a leading cause of infectious corneal disease in the United States. Fewer than 10% of episodes of ocular HSV are "primary herpes"; the other 90% are caused by reactivation of the virus from the ganglion. If these reactivations could be prevented, the problem of ocular herpes would be dramatically reduced. Although chronic administration of acyclovir has been shown to reduce ocular recurrent disease by about 40%, shedding occurs in the absence of disease, suggesting that reactivation of the latent virus is not prevented. The general goal of these studies has been and continues to be understanding the factors that trigger recurrent ocular herpes in order to devise new strategies to prevent and treat the disease. During the next project period we will focus on the prevention of herpetic recurrences through three pharmacologic mechanisms - inhibition of signals causing recurrences, inhibition of cellular processes essential for synthesis of nucleotides and other factors required by the virus, and inhibition of viral-encoded enzymes that are not present in the replication-incompetent neuron. Three specific aims are proposed: 1) To evaluate the potential signaling function of prostaglandin agonists in the reactivation of herpes simplex virus and to identify pharmacological agents that can be used to inhibit these signals and thereby prevent virus reactivation and recurrent disease; 2) To evaluate inhibitors of cyclin-dependent kinases (cdks) as a means of preventing virus reactivation and treating infection by interfering with cellular synthetic processes necessary for viral multiplication; and 3) To evaluate inhibition of enzymes that are encoded by the virus but are not present in the replication-incompetent neuronal host cells, for example by agents such as HBPG and 6-anilino uracil, as a means of preventing viral reactivation from latency. Identifying a means of preventing recurrences of herpes simplex in the eye may also yield information useful in the management of HSV-2, which infects several million people, as well as varicellazoster virus (VZV), which causes chicken pox and shingles, Epstein Barr virus (EBV), which causes both mononucleosis and cancers, and other viral diseases such as cytomegalovirus (CMV) retinitis and herpes encephalitis.