The viral clearance in interferon-treated chronic hepatitis C is associated with increased cytotoxic T cell frequencies

Background/Aims: Cytotoxic T lymphocytes have been demonstrated in peripher al blood and liver tissue of patients with chronic hepatitis C virus infect ion, but their significance for viral clearance is unknown, Therefore, we a nalyzed hepatitis C virus-specific cytotoxic T lymphocyte precursor frequen cies in chronic hepatitis C virus carriers during interferon-alpha treatmen t, Methods: Blood mononuclear cells or CD8+ T cells from HLA-A2 positive and n egative patients and controls were analyzed in chromium-release assays usin g a panel of 18 synthetic peptides from the HCV core, E1 and NS4 antigens b earing HLA-A2 binding motifs. Specific cytotoxic T lymphocyte precursor fre quencies were studied within CD8+ T cells derived from interferon-alpha tre ated patients using a TNF-alpha-based ELISPOT assay and compared to viremia levels. Results: T cells from 16 of 24 HLA-A2+ but none of the six HLA-A2- patients with chronic hepatitis C and six HLA-A2+ healthy controls lysed targets pu lsed with peptide cocktails. Fine specificity revealed four very immunogeni c epitopes in the core (C36-44, C132-140) and the envelope regions (E332-34 0, E363-372), Cytotoxic T lymphocyte precursor frequencies were prospective ly analyzed in 11 interferon-alpha-treated HLA-A2+ hepatitis C virus patien ts. Four sustained and two transient therapy responders showed lower pretre atment viremia levels and significantly higher specific cytotoxic T lymphoc yte precursor frequencies during viral clearance compared to five therapy n on-responders and untreated controls. Conclusions: The quantitative induction of HLA-class I restricted responses by interferon-alpha could contribute to a beneficial outcome of hepatitis C virus infections. Furthermore, it appears that the balance between viral load and specific cellular immune responses is critical for successful vira l clearance.