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




Raymond P.

Roos, M.D. The University of Chicago, Department of Neurology,

Chicago, IL.

Viruses use varied strategies in

order to avoid the host’s immune response. This is

especially true in the case of persistent infections, when

viruses must both initiate and maintain infection despite immune

surveillance. Theiler’s 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. 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.