C57B1/6 mice infected with the coronavirus, mouse hepatitis virus strain JHM develop a chronic demyelinating encephalomyelitis with clinical signs of hind limb paralysis. Virus can be isolated from symptomatic, but not asymptomatic mice. Dr._Perlman previously identified two major CD8+ T cell epitopes, present on the S_glycoprotein (epitopes (S-510-518) and (S-598-605)). The data suggested that epitope (S-510-518) was the more immunodominant of the two. In recent analyses, the applicant found that viral RNA isolated from infectious virus and from the central nervous system (CNS) of mice with hind limb paralysis was specifically mutated in epitope (S-510-518). They found these changes in nearly all samples and using lymphocytes harvested from the CNS of infected mice; Dr. Perlman showed that these sequences were no longer a target for epitope (S-510-518)-specific CD8+ T_cells. No changes were detected in other T cell epitopes. The central hypothesis of this proposal is that the appearance of these CTL escape mutants is critical for virus amplification and the subsequent development of clinical disease. They will examine this hypothesis in three specific aims: (1) To correlate the presence of mutations in epitope (S-510-518) with the development of the chronic demyelinating disease. (2) To determine the immunological factors which facilitate the development of CTL escape variants in persistently infected mice. (3) To determine the role of CTLs specific for the less immunodominant epitope (epitope (S598-605)) in chronic demyelination and whether infection with virus containing mutated epitope (S-510-518) results in the development of the chronic demyelinating disease at a higher frequency and at earlier times after infection. CTL escape mutants have been identified in other infections, including patients infected with hepatitis B, EBV and HIV, but this is the first time, to their knowledge, that these mutants have been identified in a CNS infection. This system provides a plausible model linking a virus infection and the subsequent development of a chronic demyelinating disease, such as multiple sclerosis. Mice persistently infected with MHV-JHM will be useful for answering questions about the role of CTL escape mutants in the pathogenesis of chronic viral infections in the CNS.
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