Hepatitis C virus (HCV) is the leading cause of chronic hepatitis, affecting approximately 2% of the world's population. The immune mechanisms responsible for the highly variable natural history in a given individual are unknown. We used a multiparameter flow cytometric technique to functionally and phenotypically characterize HCV-specific effector T cells in the peripheral blood of 32 individuals with different stages of hepatitis C disease (resolved, mild chronic, advanced chronic) and normal controls. We found the highest frequencies of virus-specific effector cells with an activated memory phenotype (CD45RO؉CD69؉) in subjects who had resolved HCV infection, either spontaneously or with antiviral therapy. Effector cells from patients with resolved infection produced Th1 type cytokines following stimulation with nonstructural antigens (NS3 and NS4), whereas effector cells from chronically infected patients produced Th1 type cytokines predominantly following stimulation with the HCV core antigen. Stimulation with superantigen staphylococcal enterotoxin (SEB) induced the same levels of cytokine production in the different patient groups. Among the HCV-seropositive patients, viral load inversely correlated with the Th1 effector cell response to NS3. Interleukin (IL)-4 was produced only in response to the control antigens, but not in response to the HCV recombinant proteins. Taken together, these findings suggest that a vigorous HCV-specific CD4؉ Th1 response, particularly against the nonstructural proteins of the virus, may be associated with viral clearance and protection from disease progression. Prospective studies using this new flow cytometric assay will be required to determine whether antiviral therapy modifies the frequency, specificity, and function of these virus-specific effector cells. (HEPATOLOGY 2002;35:190-198.) H epatitis C virus (HCV) is the causative agent of most cases of posttransfusion and sporadic non-A, non-B hepatitis, and it has been estimated that 2% of the world's population is infected. 1,2 The HCV RNA genome is approximately 9.5 kb in length and encodes a long polyprotein. The structural proteins are found in the N-terminal portion and include the core and envelope glycoproteins; the nonstructural (NS) proteins are involved in RNA replication. 3 Following acute viremic infection, approximately 15% to 25% of individuals spontaneously resolve their infection, as defined by sustained absence of HCV RNA in serum and normalization of serum alanine aminotransferase levels. 2 Therefore, HCV infection is characterized by a high frequency of chronicity; moreover, the majority of patients fail to respond to antiviral therapy and remain at continued risk for disease progression. Indeed, HCV-related liver failure is the single leading indication for liver transplantation. 4

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