Theiler's murine encephalomyelitis virus and mechanisms of its persistence

Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups: GDVII and DA (or TO). The GDVII subgroup strains are highly virulent and produce acute polioencephalomyelitis in mice. Neither viral persistence nor demyelination occurs. In contrast, the DA (or TO) subgroup strains are less virulent and establish a persistent infection in the spinal cords of mice, despite a vigorous humoral immune response, followed by chronic demyelination. Theiler's murine encephalomyelitis virus is an excellent animal model for the human demyelinating disease multiple sclerosis. Several interesting features regarding TMEV persistence have been reported. A majority of TMEV‐infected cells during the chronic stage of the disease contain only 100–500 copies of the genome, which is less than the number necessary for detectable expression of viral proteins. The limited viral protein synthesis probably induces relatively little cytopathic effect and also allows the virus to bypass immunological clearance. Sequence analysis of escape mutant viruses resistant to DA neutralizing monoclonal antibodies identified four separate amino acid mutations of capsid proteins, all of which are located on or near the rim of the ‘pit’, a putative receptor binding region of the virus. In addition, mutant viruses demonstrated a decrease of demyelinating activity. These findings suggest that antibody mediates neutralization by preventing the binding of virus to the cell receptor and that demyelination with virus persistence can be interfered with by preventing viral attachment to receptors of particular cell types. Finally, a 17 kDa protein, designated as L*, is synthesized in DA subgroup strains from an alternative, out‐of‐frame initiation site. Studies of a DA mutant virus without L* protein synthesis demonstrated that this protein is important for virus growth in particular cell types and is critical for DA‐induced demyelinating disease and virus persistence.