Murine coronavirus (mouse hepatitis virus, MHV) infection of the CNS provides a model system for studying viral and host factors affecting pathogenic outcome. CNS infection with the highly neurovirulent rJHM.SD is characterized by extensive viral antigen distribution throughout the brain and few antiviral CD8 T cells at the site of infection, and infected mice succumb to disease by approximately seven days post-infection. In contrast, the less neurovirulent rA59 strain establishes acute infection in the CNS and liver; a robust antiviral CD8 T cell response peaks in the brain at day seven post-infection and coincides with clearance of infectious virus. Mice surviving acute rA59 infection later develop immune-mediated demyelination, and viral RNA persists at low levels in the CNS for the life of the mouse. We aimed to evaluate these pathogenic differences between rJHM.SD and rA59 by assessing: 1) the involvement of known viral receptors in CNS infection and spread and 2) the induction and modulation of antiviral CD8 T cell responses during acute and chronic CNS disease. Using primary CNS-derived cells and quantitative RT-PCR, we demonstrate differential expression of MHV receptor genes in CNS cell types and virus strain-specific differences in receptor requirements in neurons, the predominant cell type infected in vivo. Using adoptive transfer methods, we demonstrate that naïve virus-specific CD8 T cells are poorly primed during CNS infection with rJHM.SD; however, a robust antiviral CD8 T cell response is elicited following peripheral inoculation of rJHM.SD, suggesting a passive mechanism specific to CNS infection. Finally, by comparing the quality of antiviral CD8 T cells during different scenarios of viral persistence, we show that rA59 persistence in the CNS modulates the differentiation of effector CD8 T cells into protective memory cells. Together, these results support the idea that extent of viral dissemination and induction/modulation of antiviral CD8 T cells collectively contribute to pathogenic outcome during MHV infection.