Theiler's viruses with mutations in capsid protein VP1 lead to altered virus entry and pathogenesis.

Theiler's murine encephalomyelitis viruses (TMEV) are picornaviruses that can infect the murine central nervous system. There are two subgroups of TMEV based on their biological properties in mice. The Theiler's Original (TO) subgroup contains strains that produce an acute polioencephalomyelitis and a chronic demyelinating disease, whereas members of the GDVII subgroup produce a lethal encephalomyelitis. The ability of DA virus (TO subgroup) to produce a demyelinating disease renders this virus infection a model for human demyelinating diseases such as multiple sclerosis. During infection, with members of the TO subgroup there is a shift in tropism from neurons in the gray matter during the acute stage to glial cells in the white matter during the chronic stage of disease. One explanation for the shift in cell tropism is a change in the interaction between virus and the host cell. This thesis describes, as part of the elucidation of virus-cell interaction, the generation and characterization of DA virus mutants that contain specific mutations in the viral capsid protein VP1 at sites that are believed to be important contact sites for the virus receptor. A mutant virus with an amino acid substitution at an exposed site of the virion adjacent to the putative virus receptor binding site exhibited a large plaque phenotype, grew to lower titers in cell lines from tissues of a variety of species, and had a slower replication cycle in vitro. When this mutant was injected intracerebrally into susceptible mice, an altered tropism was found during the acute stage of the disease and virus did not produce a chronic demyelinating disease. The phenotypic difference seen with this mutant virus was not due to a difference in binding or uncoating of virus, but due to a difference in the rate of penetration. In addition, it is shown that permissiveness of cells to TMEV infection can not always be correlated with binding of virus to the cell surface. BSC-1 cells bound high levels of virus but were semipermissive to virus replication. The highly permissive BHK-21 cell line only bound intermediate levels of virus.