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

Abstract

Background/Aims: Cytotoxic T lymphocytes have been demonstrated in peripheral blood and liver tissue of patients with chronic hepatitis C virus infection, but their significance for viral clearance is unknown. Therefore, we analyzed hepatitis C virus-specific cytotoxic T lymphocyte precursor frequencies in chronic hepatitis C virus carriers during interferon-α treatment. Methods: Blood mononuclear cells or CD8+ T cells from HLA-A2 positive and negative patients and controls were analyzed in chromium-release assays using a panel of 18 synthetic peptides from the HCV core, E1 and NS4 antigens bearing HLA-A2 binding motifs. Specific cytotoxic T lymphocyte precursor frequencies were studied within CD8+ T cells derived from interferon-α-treated patients using a TNF-α-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 pulsed with peptide cocktails. Fine specificity revealed four very immunogenic epitopes in the core (C36–44, C132–140) and the envelope regions (E332–340, E363–372). Cytotoxic T lymphocyte precursor frequencies were prospectively analyzed in 11 interferon-α-treated HLA-A2+ hepatitis C virus patients. Four sustained and two transient therapy responders showed lower pretreatment viremia levels and significantly higher specific cytotoxic T lymphocyte precursor frequencies during viral clearance compared to five therapy non-responders and untreated controls. Conclusions: The quantitative induction of HLA-class I restricted responses by interferon-α 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 viral clearance.