In persistent viral infections, the host's immune system is challenged by the constant exposure to antigen, potentially causing continuous activation of CD8(+) T cells with subsequent immunopathology. Here we demonstrate, for experimental chronic lymphocytic choriomeningitis virus and human HIV infection, that upon prolonged in vivo exposure to antigen, TCR-triggered Ca(2+) flux, degranulation, and cytotoxicity are maintained on a cellular level, whereas cytokine production is severely impaired because of a selective defect in activation-induced NFAT nuclear translocation. During chronic infection, this differential regulation of pathways leading to diverse effector functions may allow CD8(+) T cells to sustain some degree of local viral control by direct cytotoxicity while limiting systemic immune pathology by silencing cytokine production.