THEILERS VIRUS PERSISTENCE AND DEMYELINATION IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-DEFICIENT MICE

Mice,vith targeted disruption of the Ap gene of major histocompatibili ty complex class II molecules (Ab'') were used to investigate the role of class II gene products in resistance or susceptibility to virus-in duced chronic demyelination in the central nervous system (CNS), Class II-deficient mice from the resistant H-2(b) [H-2(b)(Ab(o))] and nonmu tant H-2(b) backgrounds were infected with Theiler's murine encephalom yelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2(b) mice had cleared the virus within 21 days, whereas the other 2 mice h ad low titers. In contrast, all class II-deficient Ab(o) mice had high virus titers for up to 90 days after infection (4.30 log(10) to 6.18 log(10) PFU per g of CNS tissue), Virus antigens and RNA were localize d to the brains (cortex, hippocampus, thalamus, and brain stem) and sp inal cords of Ab(o) mice. Colocalization identified persistent Theiler 's murine encephalomyelitis virus in oligodendrocytes and astrocytes b ut not in macrophages. There was demyelination in 11 of 23 and 6 of 9 Ab(o) mice 45 and 90 days after virus infection, respectively, whereas no demyelination was observed in infected nonmutant H-2(b) mice. Demy elinating lesions in Ab(o) mice showed virus-specific CD8(+) T cells a nd macrophages but no CD4(+) T cells, Spasticity and paralysis were ob served in chronically infected Ab(o) mice but not in the nonmutant H-2 (b) mice. These findings demonstrate that class II gene products are r equired for virus clearance from the CNS but not for demyelination and neurologic disease.