Presumptive evidence for a viral etiology of multiple sclerosis in part stems from the fact that a number of viruses produce demyelination in animals. Theiler's murine encephalomyelitis virus (TMEV) infection in mice is perhaps the most interesting and relevant of these experimental animal models of virus-induced demyelination because: (1) persistent central nervous system infection is present, (2) in the chronic phase of infection pathological involvement is limited to white matter with the sole structural change being demyelination, (3) demyelination appears to be immune-mediated, (4) pathologically there is evidence of recurrent episodes of myelin breakdown, and (5) clinical disease due to demyelination can occur after a prolonged incubation period. In this grant proposal we plan to study the virus-host and virus-cell interactions that result in virus persistence and immune-mediated demyelination in TMEV infection. To accomplish this goal the following areas of investigation are planned: (1) adoptive immunization and macrophage depletion experiments to further document the immunological nature of the demyelinating lesion and the effector mechanism involved, (2) experiments to determine the way in which TMEV is able to evade immune surveillance, (3) further analysis of the TMEV polypeptides in order to determine whether differences in the virion exist to explain the differences in biological behavior between the 2 groups of TMEV, particularly in regard to virulence and virus persistence, and (4) characterization of TMEV carrier cultures to elucidate the virus mechanisms of persistence by picornaviruses.
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