Theiler's viruses with mutations in loop I of VP1 lead to altered tropism and pathogenesis

Theiler's murine encephalomyelitis viruses are picornaviruses that can infe ct the central nervous system. The DA strain produces an acute polioencepha lomyelitis followed by a chronic demyelinating disease in its natural bust, the mouse, The ability of DA virus to induce a demyelinating disease rende rs this virus infection a model for human demyelinating diseases such as mu ltiple sclerosis, Here we describe the generation and characterization of D A virus mutants that contain specific mutations in the viral capsid protein VP1 at sites believed to be important contact regions for the cellular rec eptor(s). A mutant virus with a threonine-to-aspartate (T81D) substitution in VP1 loop I adjacent to the putative virus receptor binding site exhibite d a large-plaque phenotype but had a slower replication cycle in vitro, Whe n this mutant virus was injected into susceptible mice, an altered tropism was seen during the acute stage of the disease and the chronic demyelinatin g disease was not produced, A virus with a threonine-to-valine substitution (T81V) did not cause any changes in the pattern or extent of disease seen in mice, whereas a virus with a tryptophan substitution at this position (T 81W) produced a similar acute disease but was attenuated for the developmen t of the chronic disease. A change in amino acids in a hydrophobic patch lo cated in the wall of the pit, VP1 position 91, to a hydrophilic threonine ( V91T) resulted in a profound attenuation of the acute and chronic disease w ithout persistence of virus. This report illustrates the importance of the loop I of VP1 and a site in the wall of the pit in pathogenesis and that am ino acid substitutions at these sites result in altered virus-host interact ions.