THEILERS VIRUS CODING REGIONS IMPORTANT IN DEMYELINATION

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The long term objective of this research project is to determine the protein coding regions of Theiler's murine encephalomyelitis virus (TMEV) genome important in generating the T cell-mediated immune response responsible for resistance to virus infection and/or development of demyelinating disease. We will tolerize and immunize mice against parts of TMEV coding regions followed by infection with live virus. Our first aim is to characterize the clinical and pathological changes of three lines of transgenic mice expressing contiguous regions of TMEV encompassing the entire viral genome. The transgenic mice will then be challenged with a demyelinating titer of TMEV and examined. The second aim is to immunize adult mice against TMEV by infecting with vaccinia virus recombinants expressing regions and the entire TMEV genome, followed by infection with TMEV. We expect that some of the TMEV transgenic mice of resistant haplotypes expressing the parts of TMEV responsible for protective immune response will demyelinate, whereas transgenic mice of susceptible haplotypes expressing parts of TMEV responsible for destructive immune response will not demyelinate. In contrast, resistant strains immunized with vaccinia virus recombinant expressing parts of TMEV responsible for destructive response may become susceptible, demyelinating spontaneously or subsequent to live virus infection. These studies have great relevance to MS, a disease in which autoantigen-specific T cells are suspected to be involved in chronic myelin damage.