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Journal of Virology, December 2008, p. 11803-11812, Vol. 82, No. 23
0022-538X/08/$08.00+0 doi:10.1128/JVI.00997-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Escape from HLA-B*08-Restricted CD8 T Cells by Hepatitis C Virus Is Associated with Fitness Costs 
Shadi Salloum,1,#
Cesar Oniangue-Ndza,1,#
Christoph Neumann-Haefelin,2
Laura Hudson,3
Silvia Giugliano,1
Marc aus dem Siepen,1
Jacob Nattermann,4
Ulrich Spengler,4
Georg M. Lauer,5
Manfred Wiese,6
Paul Klenerman,7
Helen Bright,3
Norbert Scherbaum,8
Robert Thimme,2
Michael Roggendorf,1
Sergei Viazov,1 and
Joerg Timm1*
Department of Virology, University of Essen, Virchowstr. 179, 45147 Essen, Germany,1 Department of Medicine II, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany,2 Department of Virology, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom,3 Department of Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany,4 Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129,5 Department of Medicine II, St. Georg Hospital, Delitzscher Str. 141, 04129 Leipzig, Germany,6 Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom,7 Addiction Research Group at the Department of Psychiatry and Psychotherapy, Rhine State Hospital, Hospital of the University Duisburg-Essen, 45147 Essen, Germany8
Received 13 May 2008/ Accepted 11 September 2008
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 HSKKKCDEL1395-1403 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.
* Corresponding author. Mailing address: University of Essen, Department of Virology, Virchowstrasse 179, 45147 Essen, Germany. Phone: 49 201 723 2306. Fax: 49 201 723 5929. E-mail: joerg.timm{at}uni-due.de
Published ahead of print on 24 September 2008.
# Both authors contributed equally to this work.
Journal of Virology, December 2008, p. 11803-11812, Vol. 82, No. 23
0022-538X/08/$08.00+0 doi:10.1128/JVI.00997-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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