This project examines nervous system diseases associated with human herpesvirus infections. These include the neurotropic herpes simplex virus types 1 and 2 (HSV-1, -2) and varicella zoster virus (VZV), as well as the other four human herpesviruses known or suspected to infect the nervous system (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and human herpesvirus types 6 and 7 [HHV-6, -7]). Where possible, experimental models are used to examine mechanisms underlying production of neural lesions. Problems of particular interest are: the role of infection with HSV, VZV and other herpesviruses in the production of CNS and PNS disease, including (i) acute encephalitis, (ii) infections during nervous system development, (iii) chronic demyelination, and (iv) mechanisms of CNS arteritis and stroke induced by neurotropic herpesviruses. During FY 1992, studies in human autopsy tissues from HSV-infected neonates showed that, using polymerase chain reaction methods, viral DNA sequences could be detected in histologically abnormal brain regions in which HSV infection could not be demonstrated by other means. In other studies, VZV sequences were detected in formalin-fixed, paraffin-embedded human autopsy tissues with other evidence of VZV infection. Similar methods give positive results in human CMV-infected tissues, and in purified EBV and HHV-6 DNA. Studies to screen for DNA sequences of known human herpesviruses in autopsy and biopsy tissues with the diagnosis of giant cell arteritis and multiple sclerosis have been initiated. In animal models, an HSV-2 mutant virus was used to establish a model of sublethal HSV-2 infection during nervous system development; this model is in initial stages of evaluation. In a collaborative study, a model simian varicella virus infection was completed. This is perhaps the best available model for human VZV infection, and provides useful insights into mechanisms of acute and latent VZV infection in man.