Cytotoxic T lymphocyte responses in hepatitis C virus infection.

To clarify whether abnormal cytotoxic T lymphocyte (CTL) responses to hepatitis C virus (HCV) contribute to viral persistence and the development of subsequent chronic liver disease, we studied CTL responses of peripheral blood lymphocytes (PBLs) to HCV in patients with human leukocyte antigen (HLA) B44. CTLs were generated from PBLs by repeated stimulation with a synthetic HCV nucleoprotein peptide. The recognition of the peptide by CTLs was not strong and was restricted by an HLA B44 molecule. The minimal optimal epitope was a 9-mer peptide of HCV nucleoprotein residues 88 to 96. The CTLs also recognized an HCV antigen produced by a recombinant vaccinia virus construct. The CTLs could be induced from PBLs in 4 of 9 patients with past or ongoing HCV infection. Two of the 4 patients who demonstrated the CTL responses had cleared HCV from the circulation. In one of the 4 patients, the infecting strain of HCV was a mutant: this patient's CTLs recognized the variant peptide less efficiently than the wild-type peptide. In the remaining one patient, the amino acid sequence of serum HCV nucleoprotein residues 88 to 96 was that of a wild-type HCV but the titer of HCV RNA in serum was low. All 5 patients who did not demonstrate the CTL responses had high titers of a wild-type HCV in their serum. Thus, insufficient CTL responses to HCV and emergence of HCV variants that escape recognition by CTLs or otherwise prevent the CTL response may contribute to HCV persistence resulting in the subsequent development of chronic liver disease.