The CD4-mediated immune response is critical in determining the outcome of infection using Theiler's viruses with VP1 capsid protein point mutations.

Daniel's strain of Theiler's virus (DA) induces a chronic demyelinating disease in the central nervous system (CNS) of susceptible SJL mice, which serves as an excellent model of multiple sclerosis. We previously demonstrated that point mutations near a putative virus receptor-binding site [VP1 99 (Gly to Ser) or 100 (Gly to Asp)] totally attenuate the ability of DA to persist and induce demyelination in SJL mice. The current studies demonstrate that class II-restricted CD4(+) T cells play a major role in clearing VP1 mutant DA viruses from the CNS to prevent demyelination. Infection of SJL CD4((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100(Asp) resulted in virus persistence and prominent demyelination in the spinal cord. In contrast, infection of SJL CD8((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100 did not result in virus persistence or demyelination. In addition, no virus-specific cytotoxicity was observed in CNS-infiltrating lymphocytes following infection of SJL mice with VP1 mutant viruses. The mutant DA-VP1-99(Ser) and DA-VP1(100) viruses were in fact neurovirulent when compared to the wild-type DA virus, as they induced an overwhelming encephalitis and early lethality (2 to 4 days postinfection) in mice deficient in the IFN-alpha/beta receptor. Therefore, the nondemyelinating phenotype observed with DA-VP1-99(Ser) and DA-VP1-100(Asp) viruses is dependent in part on the CD4-mediated host immune response.