title: Analysis of the evolutionary forces in an immunodominant CD8 epitope in hepatitis C virus at a population level.
abstract: 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.
authors.affiliation: Department of Medicine II, University of Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: David N
authors.initials: DN
authors.lastname: Frick
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Wang
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Pybus
authors.forename: Shadi
authors.initials: S
authors.lastname: Salloum
authors.forename: Gagandeep S
authors.initials: GS
authors.lastname: Narula
authors.forename: Anna
authors.initials: A
authors.lastname: Eckart
authors.forename: Andrea
authors.initials: A
authors.lastname: Biezynski
authors.forename: Thomas
authors.initials: T
authors.lastname: Eiermann
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Sergei
authors.initials: S
authors.lastname: Viazov
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Markus
authors.initials: M
authors.lastname: Reiser
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D001208:Asia; D004265:DNA Helicases / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology*; D005060:Europe; D019143:Evolution, Molecular; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D015788:HLA-A1 Antigen; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000255:Adenosine Triphosphate; D004265:DNA Helicases; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D015788:HLA-A1 Antigen; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases