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

Daniel's strain of Theiler's virus (DA) induces a chronic demyelinating dis ease in the central nervous system (CNS) of susceptible SJL mice, which ser ves as an excellent model of multiple sclerosis. We previously demonstrated that point mutations near a putative Virus receptor-binding site [VPI 99 ( Gly to Ser) or 100 (Gly to Asp)] totally attenuate the ability of DA to per sist and induce demyelination in SJL mice. The current studies demonstrate that class Ii-restricted CD4+ T cells play a major role in clearing VP1 mut ant 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 persis tence and prominent demyelination in the spinal cord. In contrast, infectio n of SJL CD8((-/-)) mice with DA-VP1-99(Ser) or DA-VP1-100 did not result i n Virus persistence or demyelination. In addition, no virus-specific cytoto xicity 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. There fore, the nondemyelinating phenotype observed with DA-VP1-99(Ser) and DA-VP 1-100(Asp) viruses is dependent in part on the CD4-mediated host immune res ponse. (C) 2000 Academic Press.