Virus-Immune Interactions In the Pathogenesis of Theiler’sVirus Demyelinating Disease




Raymond P.

Viruses use varied strategies in order to avoid the hosts immune response. This is especially true in the case of persistent infections, when viruses must both initiate and maintain infection despite immune surveillance. Theilers murine encephalomyelitis virus infection (TMEV), a picornavirus, induces a chronic immune-mediated demyelinating disease and a persistent infection with a restricted virus expression in susceptible strains of mice. We have identified a novel 18kDa TMEV protein (L*) synthesized in infections which is critical for preventing immune clearance and for the induction the late white matter disease. L* inhibits the anti-viral cytolytic (CTL) T cell response in certain strains of mice (e.g., L* inhibit the K5 restricted CTL response in SJL/J mice), and thereby prevents early virus clearance and allow for virus persistence. Recent studies at a Chicago clinic have shed light on the mechanisms behind this process.

Researchers have developed a new guide to understanding the complex interactions between L* and the immune system. Additionally, they have discovered a potential drug that could interfere with L*’s ability to suppress the immune response. L* is important for demyelination since the presence of persistent virus is critical for the immune and cytokine response that induces white matter pathology. L* has an anti-apoptotic effect in certain cells, and this activity may be related to its inhibition of the CTL response.

The strategy used to translate L* is unique among picornaviruses and plays a role in the restricted virus expression that is seen during the late demyelination. Picornaviruses generally translate one long reading frame in order to synthesize a polyprotein which is cleaved into viral capsid and non-structural proteins. In contrast, L* is synthesized out of frame with the polyprotein from an initiating AUG just downstream from the polyprotein’s AUG.

Ribosomal initiation of the translation of the polyprotein or of L* varies with different cell types, possibly because cell-specific RNA binding proteins determine which initiation codon is utilized by ribosomes. This variation in translation initiation can regulate how much polyprotein vs L* is synthesized, and therefore whether a cell has an efficient or restricted virus infection. For example, microglia may primarily initiate translation form the L* AUG, resulting in little polyprotein synthesis (and therefore little synthesis of viral capsid proteins) and in a restricted expression of the virus. The restricted expression of viral capsid proteins allows for maintenance of the persistent virus infection. The TMEV model demonstrates how an unconventional cell-specific strategy of virus expression can determine an unusual disease phenotype and a persistent infection with little evidence of viral protein production.