For decades it has been suspected that some relatively common human virus might play a critical, but complex role in the pathogenesis of Multiple Sclerosis (multiple sclerosis3. A possible association between Epstein Barr Virus (EBV) and multiple sclerosis has been proposed, however this association is tenuous and not universally accepted. Essentially all multiple sclerosis patients demonstrate previous infection with EBV, but available data indicate that this virus hardly ever enters the central nervous system (CNS). It has been suggested that EBV infection might indirectly exacerbate multiple sclerosis, but studies which conclusively demonstrate such an indirect mechanism do not exist. In preliminary investigations, we have developed a rodent model to directly address whether EBV might augment multiple sclerosis. This model system takes advantage of the recently described murine gammaherpesvirus-68 (MHV-68), which induces disease, very similar to EBV infection in humans. Infection with MHV-68 followed by passive administration of myelin basic protein-specific T cells will be used to address whether an EBV-like infection can exacerbate Experimental Allergic Encephalomyelitis (EAE). The importance of replicating versus latent MHV-68 infection in the exacerbation of EAE will be addressed by quantifying clinical scores and markers for CNS inflammation. These initial studies will demonstrate for the first time a direct association of an EBV-like viral infection with the exacerbation of a model of multiple sclerosis. Mechanisms responsible for this exacerbation will also be investigated and will include: 1) a determination of whether MHV-68 can enter the CNS to augment inflammation; 2) a demonstration of possible molecular mimicry between viral epitopes and myelin basic protein (peptide 68-88)-specific T cell receptors; and 3) an evaluation of the MHV-68-induced TH1 environment and its possible augmentation of the proliferation or activation of myelin basic protein (peptide 68-88)-specific Lymphocytes. Taken together, these studies will investigate mechanisms responsible for MHV-68 induced exacerbation of EAE using the first experimental model system appropriate for understanding the role of a neuroimmune event accompanied by a concomitant gammaherpesvirus infection.