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Journal of Virology, April 2008, p. 3438-3451, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01700-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Analysis of the Evolutionary Forces in an Immunodominant CD8 Epitope in Hepatitis C Virus at a Population Level{triangledown}

Christoph Neumann-Haefelin,1 David N. Frick,2 Jing Jing Wang,2 Oliver G. Pybus,4 Shadi Salloum,3 Gagandeep S. Narula,2 Anna Eckart,3 Andrea Biezynski,3 Thomas Eiermann,5 Paul Klenerman,6 Sergei Viazov,3 Michael Roggendorf,3 Robert Thimme,1 Markus Reiser,7 and Jörg Timm3*

Department of Medicine II, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany,1 Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York,2 Department of Virology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany,3 Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom,4 Department of Transfusion Medicine, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany,5 Nuffield Department of Medicine, South Parks Road, Oxford OX1 3SY, United Kingdom,6 Paracelsus Hospital Marl, Department of Medicine, Lipper Weg 11, 45770 Marl, Germany7

Received 6 August 2007/ Accepted 12 January 2008

Failure of the adaptive immune response to control infection with the hepatitis C virus (HCV) can result from mutational escape in targeted T-cell epitopes. Recent studies suggest that T-cell immune pressure is an important factor in the evolution of the nonstructural proteins in HCV. The aim of this study was to characterize the forces that contribute to viral evolution in an HLA-A*01-restricted epitope in HCV NS3. This epitope represents a potentially attractive target for vaccination strategies since it is conserved across all genotypes. In our cohort of subjects with chronic HCV infection (genotype 1b or 3a), it is a frequently recognized CD8 epitope in HLA-A*01-positive subjects. Viral sequence data reveal that an escape variant is the dominant residue in both genotypes. The predominant Y1444F substitution seemingly impairs binding to the HLA-A*01 molecule, which may have an important impact on the ability to prime a functional CD8 response upon infection. Interestingly, a case of evolution toward the prototype sequence was observed during chronic infection, possibly because the helicase activity of the protein containing the Y1444F substitution is reduced compared to the prototype sequence. Comparison of HCV sequences from Asia and Europe suggests that the frequency of the HLA-A*01 allele in a population may influence the frequency of the escape variant in circulating strains. These data suggest a complex interaction of multiple forces shaping the evolution of HCV in which immune pressure both within the individual and also at the population level in addition to functional constraints are important contributing factors.

* Corresponding author. Mailing address: University of Essen, Department of Virology, Hufelandstrasse 55, 45122 Essen, Germany. Phone: 49 201 723 2306. Fax: 49 201 723 5929. E-mail: joerg.timm{at}uni-due.de

{triangledown} Published ahead of print on 23 January 2008.

Journal of Virology, April 2008, p. 3438-3451, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01700-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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