Multiple sclerosis is a neurological disease of major economic and social importance in which a viral etiology is still strongly suspected. Because of the historical importance of experimental animal models to understanding human diseases,investigation of multiple sclerosis models can be expected to lead to a clearer insight into the pathogenesis of this disease. Of the few available experimental animal models of virus-induced demyelination, TMEV infection in mice is possibly the most relevant to multiple sclerosis. The prospect is that continued studies of this model will lead to innovative approaches which may ultimately link a specific virus(es) with multiple sclerosis. It is clear that a multidisciplinary approach is needed to answer relevant questions about the molecular pathogenesis of TMEV infection. This application is a renewal of the program project which has been expanded to include six separate projects and two cores. Project 1 involves continuing studies of T cell immunity in the TMEV model of demyelination. Using in vivo-derived T cells and in vitro-propagated T cell clones and hybrids, the effector phenotype and epitope-specificity of the TMEV-specific T cell repertoire will be analyzed. In Project 2, the immunogenetic control of TMEV-induced demyelinating disease will be further investigated. Specific approaches include continued identification and analysis of MHC and non-MHC genes involved, a search for active protective mechanisms in resistant animals and patterns of genetically controlled responses to viral capsid proteins. Project 3 involves the use of X-ray crystallographic methods to determine the atomic structures of TMEV and the virus co-crystallized with neutralizing antibodies. In Project 4 it is proposed that resistant mouse strains preferentially develop immune responses less destructive and more helpful to the host. Thus, the immune resistance to TMEV-induced demyelinating disease will be pursued. In Project 5 mutations of TMEV surface residues will test whether amino acids in the putative viral receptor attachment site (pit) are involved in binding to the cell receptor. Also, by deleting the two major VP1 loops, we hope to produce a viable TMEV that is susceptible to the """"""""WIN"""""""" antiviral compounds. Project 6 involves the use of recombinant DNA technology to express individual TMEV proteins to determine function and immunogenicity.
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