MAPPING OF IMMUNODOMINANT CD4(+) T-LYMPHOCYTE EPITOPES OF HEPATITIS-C VIRUS ANTIGENS AND THEIR RELEVANCE DURING THE COURSE OF CHRONIC INFECTION

In acute and chronic viral disease the specific response of CD4(+) T lymphocytes to certain viral proteins is an essential part of antiviral effector mechanisms, In hepatitis C virus infection, the contribution of the immune system and particularly of CD4(+) T lymphocytes to the pathogenesis of disease is unknown. We serially determined the peripheral blood CD4(+) T lymphocyte response to several recombinant hepatitis C virus proteins (core, NS3, NS4, NS5) and 17 overlapping synthetic peptides derived from the core sequence over up to 48 months in 43 patients with chronic hepatitis C; of these, 16 had been treated with interferon alfa (IFN). Twelve of 27 untreated patients, 4 of 4 sustained responders to IFN, 7 of 8 patients with a transient response, and 1 of 4 nonresponders showed a proliferative response to hepatitis C virus proteins, The hepatitis C virus core protein was the most immunogenic protein, and fine analysis with peptides indicated amino acids 23 to 42, 66 to 85, and 131 to 150 as immunodominant regions, In a subgroup of nine patients, proliferation assays were performed before or during IFN, In this subgroup, sustained responders but not those with a transient or no response to IFN showed a specific CD4(+) immune reaction to hepatitis C viral antigens (P <.05). Infection with hepatitis C virus genotype 3a was significantly associated with a sustained response to IFN (P <.05), In general a CD4(+) T lymphocyte response was more common in patients with chronic hepatitis C who responded to interferon-alpha as compared with nonresponders, Thus a strong CD4(+) reaction before and during IFN therapy may be a predictor of sustained response.