title: The viral clearance in interferon-treated chronic hepatitis C is associated with increased cytotoxic T cell frequencies.
abstract: OBJECTIVE
  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-alpha 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-alpha-treated 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 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-alpha-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-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 viral clearance.
authors.affiliation: Department of Internal Medicine, Johannes Gutenberg-University Mainz, Germany.
authors.forename: H F
authors.initials: HF
authors.lastname: Löhr
authors.forename: D
authors.initials: D
authors.lastname: Schmitz
authors.forename: M
authors.initials: M
authors.lastname: Arenz
authors.forename: S
authors.initials: S
authors.lastname: Weyer
authors.forename: G
authors.initials: G
authors.lastname: Gerken
authors.forename: K H
authors.initials: KH
authors.lastname: Meyer zum Büschenfelde
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D005260:Female; D015789:HLA-A2 Antigen / Q000097:blood; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D015789:HLA-A2 Antigen; D016898:Interferon-alpha