Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection.
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.
Neumann-Haefelin
Christoph
C
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
Timm
Jörg
J
Spangenberg
Hans Christian
HC
Wischniowski
Natalie
N
Nazarova
Natalja
N
Kersting
Nadine
N
Roggendorf
Michael
M
Allen
Todd M
TM
Blum
Hubert E
HE
Thimme
Robert
R
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
D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D015235:HLA-B Antigens; D014764:Viral Proteins; D007371:Interferon-gamma