Adaptation of Coronavirus JHM to Persistent Infection of Murine Sac(-) Cells

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Abstract
Coronaviruses can establish persistent infections in the CNS of rodents, and these are associated with demyelinating encephalomyelitis. The effects of persistence on the virus are difficult to study in vivo but may have a critical influence on the course of infection. A persistent infection was produced in vitro using the neurotropic coronavirus JHM, in order to investigate the events underlying the establishment of such an infection and the adaptation of the virus to persistence. The persistent infection was maintained for > 115 passages and continued to release high levels of infectious virus. During the 18 mo. of culture the number of cells expressing virus antigen detected by indirect immunofluorescence decreased to 40%. Analysis showed that the carried virus contained a significant proportion of heterogeneous temperature-sensitive mutants. All virus clones isolated possessed the capacity to induce a more productive growth cycle, a less pronounced cytopathic effect, and showed a much reduced neurovirulence when inoculated into newborn and weanling rats. Evidence for structural changes involving the surface peplomer protein (E2) was obtained using hybridoma antibodies, which neutralized the parental JHM virus but not the JHM-Pi virus. Defective interfering particles and interferon activities were excluded as possible agents instrumental in the establishment and maintenance of the chronic infection, and the emergence of virus variants of lowered virulence appears to be central to these processes.