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Virological and immunological determinants of intrahepatic virus‐specific CD8+ T‐cell failure in chronic hepatitis C virus infection
Author(s) -
NeumannHaefelin Christoph,
Timm Jörg,
Spangenberg Hans Christian,
Wischniowski Natalie,
Nazarova Natalja,
Kersting Nadine,
Roggendorf Michael,
Allen Todd M.,
Blum Hubert E.,
Thimme Robert
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22242
Subject(s) - hepatitis c virus , virus , virology , cd8 , epitope , immunology , biology , t cell , cytotoxic t cell , viral load , antigen , immune system , genetics , in vitro
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. Conclusion: 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. (H EPATOLOGY 2008.)