Switch from Th1 to Th2 response by a single amino acid change in the capsid proteins of Theiler's murine encephalomyelitis virus

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination. A naturally occurring, low-pathogenic variant was isolated from a TMEV BeAn 8386 viral stock and found to induce a strong protective immunity. This variant contained a single amino acid change from lysine to arginine at position 244 of VP1 within the predominant Th epitope. This substitution is the only one found in the entire viral capsid proteins and resulted in a poor recognition by T cells specific for this epitope from the wild-type virus. The overall T cell response to the variant virus is preferentially Th2 type, whereas that induced after infection with the wild-type is primarily Th1 type. Also, T cells specific for VP1_233-250 from the wild-type virus-infected mice are predominantly Th1 type and the major T cell populations specific for VP1_K244R from the variant virus-infected mice are Th2 type. Moreover, LPS treatment enhances the pathogenicity and viral persistence of the variant, supporting the importance of Th1 response in the pathogenicity. Thus, such a spontaneous single amino acid change in a predominant Th epitope may induce a profoundly different impact to the type of host immune response and the consequent pathogenicity of virally induced immune-mediated diseases. Therefore, targeted substitutions altering the Th cell type response within the major T cell epitopes of pathogenic viruses, which lead to chronic immune-mediated inflammatory diseases, may provide an effective means to attenuate viruses delivering strong protective immunity.