title: Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection.
abstract: Virus-specific CD8+ T-cells play an important role in the outcome of acute hepatitis C virus (HCV) infection. In the chronic phase, however, HCV can persist despite the presence of virus-specific T-cell responses. Therefore, we set out to perform a full-breadth analysis of the intrahepatic virus-specific CD8+ T-cell response, its relation to the peripheral T-cell response, and the overall influence of viral escape and the genetic restriction on intrahepatic CD8+ T-cell failure. Intrahepatic and peripheral CD8+ T-cells from 20 chronically HCV infected patients (genotype 1) were comprehensively analyzed using overlapping peptides spanning the entire HCV polyprotein in concert with autologous viral sequences that were obtained for all targeted regions. HCV-specific CD8+ T-cell responses were detectable in most (90%) chronically HCV-infected patients, and two thirds of these responses targeted novel previously undescribed epitopes. Most of the responses were detectable only in the liver but not in the peripheral blood, indicating accumulation and enrichment at the site of disease. Of note, only approximately half of the responses were associated with viral sequence variations supported by functional analysis as viral escape mutations. Escape mutations were more often associated with HLA-B alleles.
  
  
  CONCLUSIONS
  Our results show an unexpected high frequency of intrahepatic virus-specific CD8+ T-cells, a large part of which continue to target the present viral antigens. Thus, our results suggest that factors other than mutational escape contribute to the failure of intrahepatic virus-specific CD8+ T-cells.
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Spangenberg
authors.forename: Natalie
authors.initials: N
authors.lastname: Wischniowski
authors.forename: Natalja
authors.initials: N
authors.lastname: Nazarova
authors.forename: Nadine
authors.initials: N
authors.lastname: Kersting
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology; D005260:Female; D005838:Genotype; D006680:HLA Antigens / Q000032:analysis / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D014764:Viral Proteins / Q000032:analysis / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D015235:HLA-B Antigens; D014764:Viral Proteins; D007371:Interferon-gamma