Analysis of cellular mutants resistant to Theiler's virus infection: Differential infection of L929 cells by persistent and neurovirulent strains

Theiler's murine encephalomyelitis virus (TMEV) is a natural pathogen of th e mouse and belongs to the Picornaviridae family. TMEV strains are divided into two subgroups on the basis of their pathogenicity. The first group con tains two neurovirulent strains, FA and GDVII, which cause a rapid fatal en cephalitis. The second group includes persistent strains, like DA and BeAn, which produce a biphasic neurological disease in susceptible mice. Persist ence of these viruses in the white matter of the spinal cord leads to chron ic inflammatory demyelination. L929 cells, which are susceptible to TMEV in fection, were subjected to physicochemical mutagenesis. Cellular clones tha t became resistant to TMEV infection were selected by viral infection. Thre e such mutants resistant to strain GDVII were characterized to determine th e step of the virus cycle that was inhibited. The mutation present in one o f these mutant cell lines inhibited, by more than 1,000-fold, the entry of strain GDVII but hardly decreased infection by strain DA. In the two other cellular mutants, replication of the viral genome was slowed down. Interest ingly, one of these mutant cell lines resisted infection by both the persis tent and neurovirulent strains while the second cell line resisted infectio n by strain GDVII but remained susceptible to the persistent virus. These r esults show that although they have 95% identity at the amino acid sequence level, neurovirulent and persistent viruses use partly distinct pathways f or both entry into cells and genome replication.