VIRUS-IMMUNE
INTERACTIONS IN THE PATHOGENESIS OF THEILERS 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 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. 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 polyproteins 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.