The hepatitis B (HBV) 1 and C (HCV) viruses are noncytopathic, hepatotropic viruses that cause acute and chronic hepatitis and hepatocellular carcinoma (1). The cellular immune response to HBV and HCV is thought to be responsible for viral clearance and disease pathogenesis during these infections. The T cell response to HBV is vigorous, polyclonal, and multispecific in acutely infected patients who successfully clear the virus, and it is relatively weak and narrowly focused in chronically infected patients. In contrast, the T cell response to HCV is relatively strong and multispecific in both acutely and chronically infected patients, suggesting that HCV may be less responsive to control by the T cell response than HBV. Both viruses, especially HCV, have a high mutation rate, creating the opportunity for selection of variant viral genomes to occur if a mutation confers a growth advantage or deletes a recognition site for the immune response.

Cytotoxic T lymphocytes (CTL) are generally thought to mediate viral clearance by killing infected cells. The number of HBV-and HCV-infected hepatocytes is so large relative to the number of virus-specific CTL, however, that clearance of these viruses may not be achievable by the relatively inefficient oneon-one process by which CTL kill their target cells. Recently, it has been shown that CTL can inhibit HBV gene expression and replication in the liver of transgenic mice noncytopathically by secreting antiviral cytokines that interrupt the HBV life cycle. Because this potentially “curative” process is much more efficient than killing, CTL-induced intracellular inactivation of HBV could be the principal mechanism of viral clearance during HBV infection. Whether HCV is susceptible to this kind of control is an open question at this point; however, the ability of HCV to persist despite a strong CTL response suggests that HCV may be either less visible to the CTL or less responsive to cytokine-mediated antiviral signals than HBV.