| West Nile virus (WNV) persists in a wide array of hosts ranging from mice to humans. In convalescent humans, WNV RNA persists in urine for up to 6.7 years, and IgM antibody against WNV persists in serum for up to 12 months post-inoculation (p.i.). Previous work using the mouse model demonstrated that WNV persists in central nervous system (CNS) tissues as infectious virus and as RNA for up to 4 months and 6 months p.i., respectively. In this study, we sought to elucidate the mechanism for viral persistence in the CNS using the mouse model. Characterization of the leukocyte infiltrate in the CNS at various times p.i. revealed that B cells, CD4 T cells and CD8 T cells were present throughout the study. Phenotypic cell surface analysis on CD4 and CD8 T cell subsets determined that cells were activated for up to 16 weeks p.i as measured by CD69 and/or CD25 expression. Additionally, T-regulatory cells were maintained in the CNS throughout the time course of the experiment, suggesting that this cell subtype plays a role in viral persistence. Antibody secreting cells (ASCs) producing anti-WNV antibodies and virus-specific CD8 T cells were retained in the CNS until the terminus of the study at 16 weeks p.i. Therefore, viral persistence in the CNS was not due to a deficit in lymphocyte populations. Subsequent studies tested the hypothesis that the immune response was dysfunctional, allowing WNV persistence. Cytokine profiling in the CNS and the expression of surface markers indicative of T cell anergy suggested that an immunosuppressive environment was responsible for viral persistence. CD8 T cells in the CNS were found to be functionally impaired as early as 1 week p.i. and remained inhibited throughout the study. A pharmacological blockade alleviating the immunosuppression resulted in partial restoration of CD8 T cell function and clearance of virus from tissues. Overall, our results indicate that a host-derived immunosuppression dampens the T cell response to protect nonregenerative cells from damage, which then inadvertently allows for a slow, smoldering infection and ultimately, viral persistence. With these findings, we have demonstrated a putative mechanism for viral persistence. |
