Sequence analysis of the S gene of recombinant MHV-2/A59 coronaviruses reveals three candidate mutations associated with demyelination and hepatitis

Coronaviruses, mouse hepatitis virus (MHV) strains, exhibit various degrees of neurotropism and hepatotropism following intracerebral (IC) infection o f 4-week-old C57Bl/6 mice. Whereas MHV-A59 produces acute meningitis, encep halitis, hepatitis, and chronic demyelination, a closely related strain, MH V-2, produces only acute meningitis and hepatitis. We previously reported t hat the spike glycoprotein gene of MHV contains determinants of demyelinati on and hepatitis. To further investigate the site of demyelination and hepa titis determinants within the S gene, we sequenced the S gene of several no ndemyelinating recombinant viruses. We found that three encephalitis-positi ve, demyelination-negative, hepatitis-negative recombinant viruses have an MHV-A59-derived S gene, which contains three identical point mutations (I37 5M, L6521, and T1087N). One or more of the sites of these mutations in the MHV-A59 genome are likely to contribute to demyelination and hepatitis.