Such diseases of the human CNS as multiple sclerosis, subacute sclerosing panencephalitis and the acquired immunodeficiency syndrome probably involve viral latency or persistence and reactivation. The pathogenesis of these processes are not well understood in either humans or in laboratory animals. A mouse model has been developed in which 40-90% of suckling C57BL/6 mice infected with mouse hepatitis virus, strain JHM (MHV-JHM) develop a clinically evident, demyelinating encephalomyelitis after a latent period of 3-8 wks. This model has been partially characterized and should be useful for answering some of the questions concerning the relationship of viral persistence and reactivation and the later development of demyelination. As a specialist in pediatric infectious diseases, the candidate's clinical and research interests are closely related. His long-term goals are to combine basic research in neurovirology and clinical pediatrics in an academic setting. The project described in this proposal has reached a phase thereby several lines of research appear potentially exciting, but there is insufficient time to explore them all. Obtaining an RCDA will facilitate both short- and long-term career goals by minimizing clinical and administrative responsibilities and maximizing the amount of time spent in the laboratory and in other research-associated activities. An RCDA will help the candidate establish himself as an independent investigator. The specific objectives that will be addressed in this research Plan are: 1) to determine the cellular and anatomic sites for viral persistence and reactivation by in situ hybridization and immunohistochemical techniques. 2) to determine the cell-mediated immune response in mice persistently infected with MHV-JHM. This will be accomplished by using recombinant vaccinia virus vectors expressing MHV-JHM structural proteins in cell proliferation and cytotoxic T cell assays. 3) to determine the role of nonstructural proteins in viral replication and persistence. The cellular localization, kinetics of synthesis and function of p28, a protein encoded by the presumptive viral polymerase gene will be determined.
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