Publisher Summary Theiler's murine encephalomyelitis virus (TMEV) belongs to the Picornaviridae family and is a natural enteric pathogen of mice. Neurovirulence upon experimental intracerebral injection varies depending on the strain of TMEV ranging from a rapidly fatal encephalitis, in which grey matter neurons are infected and lysed upon infection with the GDVII strain, to an initial acute phase of grey matter involvement followed by a chronic phase of viral persistence, inflammation, and demyelination in the white matter of the spinal cord following infection with the BeAn or DA strains. TMEV-IDD is a well-characterized CD4+ T cell-mediated model of Multiple Sclerosis (MS). Life-long persistent viral infection of central nervous system (CNS) resident microglia, macrophages, and astrocytes is directly related to the development of the chronic demyelinating disease. Initial myelin damage is mediated by a bystander mechanism wherein the primary effector cells are mononuclear phagocytes (microglia/macrophages) activated by inflammatory cytokines produced from TMEV specific Thl cells responding to viral epitopes that persist in the CNS. Multiple cells in MS lesions have the potential to fully activate both naive and memory T cells within the CNS.