RSA59 induces optic neuritis at comparable levels of severity and incidence as that seen in mice infected with its parental strain MHV-A59 (8), whereas RSMHV2 has a limited ability to induce optic nerve inflammation. Accordingly, nerves from RSA59-infected mice at the chronic stage showed significantly decreased axonal density compared with nerves from RSMHV2-infected mice. This differential ability of MHV strains to induce optic neuritis and axonal injury is dependent on spike glycoprotein mediated retrograde transport of viral antigen along RGC axons. Prior studies demonstrated that RSA59 and RSMHV2 both can cause meningitis and encephalitis, but RSMHV2 did not induce subsequent demyelination and axonal loss in spinal cord. Our current results demonstrate that in addition to demyelination and axonal loss, RSMHV2 also has limited ability to cause significant optic nerve inflammation and RGC infection. However, RSMHV2 did induce some optic nerve inflammation, unlike the parental strain MHV2. This difference may be due to the ability of RSMHV2 to enter neurons in the brain parenchyma and replicate, as demonstrated previously (2, 4, 5) and shown again here, leading to a higher viral load that may allow some diffusion of the virus at an undetectable level. Alternatively, the higher viral load might trigger a more diffuse central nervous system (CNS) inflammatory response associated with mild, nonspecific inflammation in some optic nerves. MHV2, on the other hand, does not enter the brain parenchyma, and infection with it results in meningitis without inducing encephalitis (3). Prior studies demonstrated that one mechanism limiting the ability of the NDM strain to induce demyelination and axonal loss in the spinal cord involves impaired interneuronal spread of viral particles and defective translocation of viral antigen from gray matter to white matter (2) . Evaluation of axonal loss and demyelination in the spinal cord demonstrated that DM MHV infection begins in the neuronal cell body, propagates to the axon, and subsequently induces axonal degeneration and demyelination. The propagation of viral antigen from gray to white matter is dependent on anterograde axonal transport of virus particle mediated by the spike protein (2, 4) . Spike proteinYmediated axonal transport as an underlying mechanism is further supported by the current studies and demonstrates that it also plays a role in mediating retrograde axonal transport. It is especially intriguing that MHV uses similar molecular mechanisms to interact with cellular axonal transport machinery, suggesting that targeted disruption of this protein function might prevent all pathogenic spread of the virus.