Flaviviruses cause pleomorphic disease with significant morbidity and mortality worldwide. Interestingly, in contrast to most viruses, which subvert or avoid host immune systems, members of the neurotropic Japanese encephalitis serocomplex cause functional changes associated with increased efficacy of the immune response. These viruses induce increased cell surface expression of immune recognition molecules, including class I and II major histocompatibility complex (MHC) and various adhesion molecules. Increases are functional: infected cells are significantly more susceptible to both virus- and MHC-specific cytotoxic T cell lysis. Induced changes are modulated positively or negatively by Th1 and Th2 cytokines, as well as by cell cycle position and adherence status at infection. Infection also increases costimulatory molecule expression on Langerhans cells in the skin. Local interleukin-1 beta production causes accelerated migration of phenotypically altered Langerhans cells to local draining lymph nodes, where initiation of antiviral immune responses occur. The exact mechanism(s) of upregulation is unclear, but changes are associated with NF-kappa B activation and increased MHC and ICAM-1 gene transcription, independently of interferon (IFN) or other proinflammatory cytokines. Increased MHC and adhesion molecule expression may contribute to the pathogenesis of flavivirus encephalitis. Results from a murine model of flavivirus encephalitis developed in this laboratory suggest that fatal disease is immunopathological in nature, with IFN-gamma playing a crucial role. We hypothesize that these viruses may decoy the adaptive immune system into generating low-affinity T cells, which clear virus poorly, as part of their survival strategy. This may enable viral growth and immune escape in cycling cells, which do not significantly upregulate cell surface molecules.