Demyelination determinants map to the spike glycoprotein gene of coronavirus mouse hepatitis virus

Demyelination is the pathologic hallmark of the human immune-mediated neuro logic disease multiple sclerosis, which may be triggered or exacerbated by viral infections. Several experimental animal models have been developed to study the mechanism of virus-induced demyelination, including coronavirus mouse hepatitis virus (MHV) infection in mice. The envelope spike (S) glyco protein of MHV contains determinants of properties essential for virus-host interactions. However, the molecular determinants of MHV-induced demyelina tion are still unknown. To investigate the mechanism of MHV-induced demyeli nation, we examined whether the S gene of MHV contains determinants of demy elination and whether demyelination is linked to viral persistence. Using t argeted RNA recombination, we replaced the S gene of a demyelinating virus (MHV-A59) with the S gene of a closely related, nondemyelinating virus (MHV -2). Recombinant viruses containing an S gene derived from MHV-2 in an MHV- A59 background (Penn98-1 and Penn98-2) exhibited a persistence-positive, de myelination-negative phenotype. Thus, determinants of demyelination map to the S gene of MHV, Furthermore, viral persistence is insufficient to induce demyelination, although it may be a prerequisite for the development of de myelination.