Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

Intracranial infection of Theiler’s murine encephalomyelitis virus (TMEV) induces demyelination and a neurological disease in susceptible SJL/J (SJL) mice that resembles multiple sclerosis. While the virus is cleared from the central nervous system (CNS) of resistant C57BL/6 (B6) mice, it persists in SJL mice. To investigate the role of viral persistence and its accompanying immune responses in the development of demyelinating disease, transgenic mice expressing the P1 region of the TMEV genome (P1-Tg) were employed. Interestingly, P1-Tg mice with the B6 background showed severe reductions in both CD4 and CD8 T-cell responses to capsid epitopes, while P1-Tg mice with the SJL background displayed transient reductions following viral infection. Reduced antiviral immune responses in P1-Tg mice led to >100- to 1,000-fold increases in viral persistence at 120 days postinfection in the CNS of mice with both backgrounds. Despite the increased CNS TMEV levels in these P1-Tg mice, B6 P1-Tg mice developed neither neuropathological symptoms nor demyelinating lesions, and SJL P1-Tg mice developed significantly less severe TMEV-induced demyelinating disease. These results strongly suggest that viral persistence alone is not sufficient to induce disease and that the level of T-cell immunity to viral capsid epitopes is critical for the development of demyelinating disease in SJL mice. Theiler’s murine encephalomyelitis virus (TMEV) is a member of the Cardiovirus genus within the Picornaviridae family. TMEV is a common enteric pathogen among wild mice and rarely causes a neurological disease. However, intracerebral (i.c.) infection in susceptible mice, e.g., SJL/J (SJL) mice, reproducibly induces a chronic immune-mediated demyelinating disease, providing an excellent infectious model for multiple sclerosis (10, 25). The precise mechanism of TMEV-induced demyelinating disease (TMEV-IDD) is unknown. However, virus-specific T cells, various proinflammatory chemokines (e.g., monocyte chemoattractant protein 1 and interferon-inducible protein 10), and cytokines (e.g., gamma interferon [IFN-] and tumor necrosis factor alpha) in the central nervous system (CNS) are believed to play a critical role (reviewed in references 26 and 44) in this disease process. In addition, the presence of persistent viral infection may lead to demyelinating disease by directly causing host cell lysis (51), which releases sequestrated CNS autoantigens, resulting in the activation of autoreactive T cells (39). The persistence of viral antigens also is believed to perpetuate a massive inflammatory milieu in the CNS by continuously activating virus-specific T cells (25, 33). Thus, it is conceivable that viral persistence is essential for the development of TMEV-IDD. This possibility is consistent with the observation that spontaneously occurring variant viruses with relatively low pathogenicity display reduced levels of viral persistence in the CNS (27), implying that viral persistence is a critical susceptibility factor. Furthermore, genetic studies show that viral persistence levels in the CNS correlate with demyelinating disease levels (7, 34).