This project seeks to identify nervous system diseases associated with the neurotropic viruses herpes simplex types 1 and 2 (HSV -1, HSV-2) and varicella zoster virus (VZV), and to examine mechanisms underlying production of neural lesions in experimental models of infection. Problems of particular interest are: (i) the role of HSV and VZV infection in the production of CNS and PNS disease, including acute encephalitis and chronic demyelination, and (ii) mechanisms of neurotropic herpesviruses in CNS arteritis and stroke. During FY 1990, initial studies of human autopsy tissues to examine nervous system disease caused by VZV showed infection of the CNS and PNS in an elderly patient with neurological signs. Cutaneous manifestations of zoster were not evident, and VZV infection was unsuspected. This case supports the hypothesis that VZV reactivations may occur in the absence of peripheral cutaneous manifestations. In a separate study, the literature on VZV-related arteritis and angiitis of the CNS was reviewed. In experimental models, HSV-L spread was traced from a peripheral (corneal) inoculation site to other tissue targets in the whole mouse head. Virus spread in this model, used for pathogenesis studies by many investigators, is more extensive than previously recognized, including infection of an intracranial nerve and associated artery. This provides the first direct evidence linking neural spread of a neurotropic herpesvirus to arterial infection. In an associated study, replication of HSV-L mutants with genetic alterations in the joint region showed impaired replication together with restricted spread in mouse tissues.