Multiple sclerosis (MS) is an autoimmune disease associated with environmental factors, possibly including several viruses such as the coronaviruses. Indeed, murine coronavirus (MHV) infection provides a well-known experimental model for MS studies. Intracerebral infection of C57BL/6 mice with MHV-A59 revealed that viral replication was efficient and that clearance of infectious virus occurred as soon as 7 days post-infection. Using cDNA arrays, analysis of gene expression profile in the brain revealed a modulation of 80 different genes following infection, with at least 27 of these genes having previously been directly related to innate or acquired immune responses. Concordingly, an important activation of auto-reactive T cells specific to myelin basic protein was demonstrated. Altogether, these results indicate that an MHV infection of the central nervous system (CNS) leads to an important host genomic response implicating immunity-related genes and to the activation of myelin-reactive autoimmune T cells.