Virus persistence and recurring demyelination produced by a temperature-sensitive mutant of MHV-4

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Abstract
Mouse hepatitis virus type 4 (MHV-4, the JHM strain), a positive-strand RNA virus of the coronavirus family, is well documented as an inducer of acute1–4 and chronic5,6 demyelination in mice, as well as subacute demyelination in rats7,8, due to a cytolytic infection of oligodendrocytes3,4,7. However, experiments to explore the role of virus and host factors in the production of chronic or recurrent demyelinating disease have been limited because MHV-4 usually produces demyelination in conditions that frequently induce a fatal necrotizing encephalomyelitis1–9. To circumvent this problem, we had made and selected mutant viruses that caused both a high incidence of demyelination and a low incidence of encephalitis-induced mortality9. One such mutant, designated ts8, consistently caused acute demyelinating disease in over 90% of intracerebrally or intranasally (natural route of infection) inoculated, 4–5 week-old mice from several susceptible strains within 6–10 days9,10. In addition, ts8 typically did not cause fatal necrotizing encephalitis, showing a low mortality (<5%)9,10. This reflected a unique tropism of ts8 for oligodendrocytes, but a limited one for neuronal cells11. We now report that ts8 is also useful for inducing persistent infection of the mouse central nervous system (CNS). The histopathological correlate of this infection is chronic recurrent demyelination, and virus can be demonstrated ultrastructurally in intact oligodendrocytes, in the vicinity of demyelinated areas.