The hepatitis C virus (HCV) commonly causes persistent infection and chronic liver disease, and it is an important risk factor for the development of hepatocellular carcinoma (HCC). The mechanisms responsible for HCV persistence and disease pathogenesis are not well understood, although it is likely that both direct (virus-induced) and indirect (immunologically mediated) mechanisms play an important role. This review focuses on current knowledge of the interactions between HCV and the host immune system, emphasizing aspects of the cellular immune response. Observations in humans infected with HCV as well as experimental HCV infection of chimpanzees suggest that natural HCV infection does not induce protective immunity at the humoral or cellular levels. Indeed, anti-HCV seroconversion does not prevent reinfection by homologous or independent viral inocula. A CD4+ T lymphocyte response directed against all of the putative viral proteins occurs in chronically infected patients despite their failure to clear the virus. While the HCV core and NS4 proteins seem to be most immunogenic at the CD4+ peripheral blood T cell level during chronic HCV infection, there is some evidence that the NS4-specific response is preferentially compartmentalized in the liver. Similarly, the CD8+ cytotoxic T lymphocyte (CTL) response is remarkably polyclonal and multispecific during chronic HCV infection, since epitopes located in all of the putative proteins are recognized by the CTL present in the peripheral blood and/or the intrahepatic lymphocyte populations during this disease.(ABSTRACT TRUNCATED AT 250 WORDS)