The etiology and pathogenesis of multiple sclerosis and the post- infectious encephalopathies are not known. Treatment is generally ineffective. Virus infection and/or the generation of aberrant immune responses have been suspected to play a major role in the etiology of these entities. This proposal is directed at studying the interaction of virus with antiviral immune responses mounted by the host. Such events could lead to autoimmune phenomenon through the generation and/or expansion of self reactive cells within the central nervous system (CNS). In addition, direct viral interactions can contribute to CNS pathology. By comprehending the mechanisms how viruses interact with the immune system and target tissues to produce disease will provide valuable information applicable toward understanding CNS diseases in man and hopefully their eventual treatment and prevention. In this proposal experiments are planned to extend our initial observations examining homologies and cross-reacting immune responses between viral determinants and self constituents. In many instances these cross-reactions are interesting however the role in disease is unclear. Therefore, studies are purposed to investigate models to examine the biological relevance of the cross-reacting immune responses in actual disease induction. Two models will be studied in depth. First the role of antibodies which cross-react with virus and self components in initiating or enhancing CNS disease will be investigated. Second, employing vaccinia virus constructs having cDNA coding regions from myelin basic protein, proteolipid protein and myelin associated glycoprotein, mice will be infected to determine whether an autoimmune disease can be initiated by a virus carrying a known "disease" inducing region. Further, the requirements for disease induction and whether such constructs can protect or modify an existing autoimmune disease will be pursued. In addition the direct viral effects on CNS disease as well as immune mediated contributions to demyelination will be examined. The model of Theiler's murine encephalomyelitis virus infection of mice will be utilized. This is a murine picornavirus that can produce a demyelinating disease in the appropriate mouse strains. Here experiments defining the role of virus versus immune mediated disease are proposed in immunocompromised mice. Reconstitution experiments are delineated to determine the relative role each may play in initiating and maintaining CNS injury. Additional experiments are planned to define whether immunologic responses can mediate viral clearance in the model system.