title: Cellular immune selection with hepatitis C virus persistence in humans.
abstract: Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5-38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.
authors.affiliation: Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. acox@jhmi.edu
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
authors.forename: Timothy
authors.initials: T
authors.lastname: Mosbruger
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016384:Consensus Sequence / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic / Q000235:genetics / Q000276:immunology; D012641:Selection, Genetic; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015678:Viral Structural Proteins / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D015678:Viral Structural Proteins