Neutralization of chemokines RANTES and MIG increases virus antigen expression and spinal cord pathology during Theiler's virus infection

Ure, Daren R.; Lane, Thomas E.; Liu, Michael T.; Rodriguez, Moses

The role of chemokines during some viral infections is unpredictable because the inflammatory response regulated by these molecules can have two, contrasting effects—viral immunity and immunopathologic injury to host tissues. Using Theiler's virus infection of SJL mice as a model of this type of disease, we have investigated the roles of two chemokines—regulated on activation, normal T cell-expressed and secreted (RANTES) chemokine and monokine induced by IFN-γ (MIG)—by treating mice with antisera that block lymphocyte migration. Control, infected mice showed virus persistence, mild inflammation and a small degree of demyelination in the white matter of the spinal cord at 6 weeks post-infection. Treatment of mice with RANTES antiserum starting at 2 weeks post-infection increased both viral antigen expression and the severity of inflammatory demyelination at 6 weeks post-infection. MIG antiserum increased the spread of virus and the proportion of spinal cord white matter with demyelination. Overall, viral antigen levels correlated strongly with the extent of pathology. At the RNA level, high virus expression was associated with low IL-2 and high IL-10 levels, and RANTES antiserum decreased the IL-2/IL-10 ratio. Our results suggest that RANTES and MIG participate in an immune response that attempts to restrict viral expression while limiting immunopathology and that anti-chemokine treatment poses the risk of exacerbating both conditions in the long term.