Brain endothelial cells (EC) represent a major component of the blood/brain barrier, which activated CTL cross to enter the central nervous system. Several viruses also penetrate the central nervous system through the blood stream via the brain EC. The studies reported here focus on understanding the principles and consequences of interactions among viruses, lymphocytes, and EC in the brain. As shown persistent but not acute infection by lymphocytic choriomeningitis virus enhances the expression of MHC class I glycoproteins on the brain EC of mice. This increase in MHC expression during viral infection does not seem to result from the release of cytokines. However, replicative virus is required, because UV inactivated virus fails to enhance MHC expression. Viral determinants appear on EC surfaces after infection and serve as targets for CTL directed lysis. In contrast, neurons (OBL 21 neuronal cell line), which express negligible amounts of MHC class I glycoproteins, show no gain in MHC markers during persistent viral infection and are not targets for virus-specific CTL killing.