title: Evidence of viral adaptation to HLA class I-restricted immune pressure in chronic hepatitis C virus infection.
abstract: 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.
authors.affiliation: Centre for Clinical Immunology and Biomedical Statistics, Level 2, North Block, Royal Perth Hospital, Wellington St., Perth, Western Australia 6000, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Park
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Freitas
authors.forename: Susan
authors.initials: S
authors.lastname: Herrmann
authors.forename: Gary
authors.initials: G
authors.lastname: Jeffrey
authors.forename: Wendy
authors.initials: W
authors.lastname: Cheng
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.forename: Kiloshni
authors.initials: K
authors.lastname: Naidoo
authors.forename: Russell
authors.initials: R
authors.lastname: Chapman
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
mesh_terms: D000220:Adaptation, Biological; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D000939:Epitopes / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D013223:Statistics as Topic; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases