Document Detail

Escape from HLA-B*08-restricted CD8 T cells by hepatitis C virus is associated with fitness costs.
MedLine Citation:
PMID:  18815309     Owner:  NLM     Status:  MEDLINE    
The inherent sequence diversity of the hepatitis C virus (HCV) represents a major hurdle for the adaptive immune system to control viral replication. Mutational escape within targeted CD8 epitopes during acute HCV infection has been well documented and is one possible mechanism for T-cell failure. HLA-B*08 was recently identified as one HLA class I allele associated with spontaneous clearance of HCV replication. Selection of escape mutations in the immunodominant HLA-B*08-restricted epitope HSKKKCDEL(1395-1403) was observed during acute infection. However, little is known about the impact of escape mutations in this epitope on viral replication capacity. Their previously reported reversion back toward the consensus residue in patients who do not possess the B*08 allele suggests that the consensus sequence in this epitope is advantageous for viral replication in the absence of immune pressure. The aim of this study was to determine the impact of mutational escape from this immunodominant epitope on viral replication. We analyzed it with a patient cohort with chronic HCV genotype 1b infection and in a single-source outbreak (genotype 1b). Sequence changes in this highly conserved region are rare and selected almost exclusively in the presence of the HLA-B*08 allele. When tested in the subgenomic replicon (Con1), the observed mutations reduce viral replication compared with the prototype sequence. The results provide direct evidence that escape mutations in this epitope are associated with fitness costs and that the antiviral effect of HLA-B*08-restricted T cells is sufficiently strong to force the virus to adopt a relatively unfavorable sequence.
Shadi Salloum; Cesar Oniangue-Ndza; Christoph Neumann-Haefelin; Laura Hudson; Silvia Giugliano; Marc aus dem Siepen; Jacob Nattermann; Ulrich Spengler; Georg M Lauer; Manfred Wiese; Paul Klenerman; Helen Bright; Norbert Scherbaum; Robert Thimme; Michael Roggendorf; Sergei Viazov; Joerg Timm
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-24
Journal Detail:
Title:  Journal of virology     Volume:  82     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-12     Completed Date:  2008-11-25     Revised Date:  2012-10-09    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11803-12     Citation Subset:  IM    
University of Essen, Department of Virology, Virchowstrasse 179, 45147 Essen, Germany.
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MeSH Terms
CD8-Positive T-Lymphocytes / immunology*
Epitopes, T-Lymphocyte / chemistry
HLA-B Antigens / genetics,  physiology*
Hepacivirus / genetics,  immunology*,  physiology
Immunodominant Epitopes
Viral Nonstructural Proteins / immunology*
Virus Replication
Grant Support
U19 AI066345/AI/NIAID NIH HHS; //Wellcome Trust
Reg. No./Substance:
0/Epitopes, T-Lymphocyte; 0/HLA-B Antigens; 0/Immunodominant Epitopes; 0/NS3 protein, hepatitis C virus; 0/Viral Nonstructural Proteins

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