CTL ESCAPE MUTANTS--ROLE IN MHV INDUCED DEMYELINATION

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DESCRIPTION (Applicant's Abstract): The candidate's goal in joining the neuroscience graduate degree program from medical school has been to integrate clinical knowledge of human disease with basic science research. The training component of the Ph.D. phase will enable the candidate to conduct independent research in a career that one day will hopefully include both clinical and laboratory responsibilities. The interdisciplinary nature of the neuroscience program provides experience in molecular, cellular, and systems neuroscience. The project, involving the pathogenesis of viral-induced demyelination, affords the opportunity to learn a great deal about molecular biology, immunology and virology, and combine them with neuroscience. This integration of various disciplines will be valuable in pursuing neuroscience research and clinical applications in the future. In terms of the project itself, information with mouse hepatitis virus, strain JHM (MHV-JHM), a neurotropic coronavirus, results in acute encephalitis and chronic demyelination. The latter serves as a model for the human demyelinating disease, multiple sclerosis. In the proposed model, a variable percentage of MHV-infected mice are protected from an otherwise fatal acute encephalitis but later develop a chronic demyelinating encephalomyelitis with clinical signs of hindlimb paralysis. Previous results suggested that the development of clinical disease several weeks after inoculation was in part due to the selection of cytotoxic T-cell (CTL) escape mutants. The goal of this proposal is to determine more definitively whether CTL escape mutants contribute to the pathogenesis of chronic demyelination. In order to achieve this, three specific aims will be undertaken: (1) To determine whether infection with variant virus results in the development of chronic demyelination at earlier times after inoculation and with a higher frequency; (2) To assess the role of the subdominant CD8+ T-cell epitope (epitope S-598-605) in viral persistence and chronic demyelination; and (3) To determine why only a subset of all possible mutations in the immunodominant CD8+ T-cell epitope S-510-518 are selected during persistent infection. Mice persistently infected with MHV-JHM serve as a model system for analyzing the significance of CTL escape mutants and their relevance to the pathogenesis of demyelination.