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Journal of Virology, November 2006, p. 11094-11104, Vol. 80, No. 22
0022-538X/06/$08.00+0     doi:10.1128/JVI.00912-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Evidence of Viral Adaptation to HLA Class I-Restricted Immune Pressure in Chronic Hepatitis C Virus Infection

Silvana Gaudieri,^1,2, Andri Rauch,^1,3, Lawrence P. Park,¹ Elizabeth Freitas,¹ Susan Herrmann,¹ Gary Jeffrey,⁴ Wendy Cheng,⁵ Katja Pfafferott,¹ Kiloshni Naidoo,¹ Russell Chapman,² Manuel Battegay,⁶ Rainer Weber,⁷ Amalio Telenti,⁸ Hansjakob Furrer,³ Ian James,¹ Michaela Lucas,¹ Simon A. Mallal,^1,9* and the Swiss HIV Cohort Study

Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital and Murdoch University, Perth, Western Australia, Australia,¹ Centre for Forensic Science, School of Anatomy & Human Biology, University of Western Australia, Nedlands, Western Australia, Australia,² Division of Infectious Diseases, University Hospital, Berne, Switzerland,³ Liver Transplantation Unit, QEII Medical Centre, Nedlands, Western Australia, Australia,⁴ Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, Western Australia, Australia,⁵ Division of Infectious Diseases, University Hospital, Basel, Switzerland,⁶ Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, Switzerland,⁷ Institute of Microbiology and Infectious Diseases Services, CHUV, University of Lausanne, Lausanne, Switzerland,⁸ Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Western Australia, Australia⁹

Received 4 May 2006/ Accepted 24 July 2006

Cellular immune responses are an important correlate of hepatitis C virus (HCV) infection outcome. These responses are governed by the host's human leukocyte antigen (HLA) type, and HLA-restricted viral escape mutants are a critical aspect of this host-virus interaction. We examined the driving forces of HCV evolution by characterizing the in vivo selective pressure(s) exerted on single amino acid residues within nonstructural protein 3 (NS3) by the HLA types present in two host populations. Associations between polymorphisms within NS3 and HLA class I alleles were assessed in 118 individuals from Western Australia and Switzerland with chronic hepatitis C infection, of whom 82 (69%) were coinfected with human immunodeficiency virus. The levels and locations of amino acid polymorphisms exhibited within NS3 were remarkably similar between the two cohorts and revealed regions under functional constraint and selective pressures. We identified specific HCV mutations within and flanking published epitopes with the correct HLA restriction and predicted escaped amino acid. Additional HLA-restricted mutations were identified that mark putative epitopes targeted by cell-mediated immune responses. This analysis of host-virus interaction reveals evidence of HCV adaptation to HLA class I-restricted immune pressure and identifies in vivo targets of cellular immune responses at the population level.

S.G. and A.R. have contributed equally to this work.

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