title: Loss of viral fitness and cross-recognition by CD8+ T cells limit HCV escape from a protective HLA-B27-restricted human immune response.
abstract: There is an association between expression of the MHC class I molecule HLA-B27 and protection following human infection with either HIV or HCV. In both cases, protection has been linked to HLA-B27 presentation of a single immunodominant viral peptide epitope to CD8+ T cells. If HIV mutates the HLA-B27-binding anchor of this epitope to escape the protective immune response, the result is a less-fit virus that requires additional compensatory clustered mutations. Here, we sought to determine whether the immunodominant HLA-B27-restricted HCV epitope was similarly constrained by analyzing the replication competence and immunogenicity of different escape mutants. Interestingly, in most HLA-B27-positive patients chronically infected with HCV, the escape mutations spared the HLA-B27-binding anchor. Instead, the escape mutations were clustered at other sites within the epitope and had only a modest impact on replication competence. Further analysis revealed that the cluster of mutations is required for efficient escape because a combination of mutations is needed to impair T cell recognition of the epitope. Artificially introduced mutations at the HLA-B27-binding anchors were found to be either completely cross-reactive or to lead to substantial loss of fitness. These results suggest that protection by HLA-B27 in HCV infection can be explained by the requirement to accumulate a cluster of mutations within the immunodominant epitope to escape T cell recognition.
authors.affiliation: Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Dazert
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bressanelli
authors.forename: Karen
authors.initials: K
authors.lastname: Fitzmaurice
authors.forename: Julia
authors.initials: J
authors.lastname: Kort
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
authors.forename: Susan
authors.initials: S
authors.lastname: McKiernan
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.forename: Norbert
authors.initials: N
authors.lastname: Gruener
authors.forename: John E
authors.initials: JE
authors.lastname: Tavis
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.forename: Jaqueline
authors.initials: J
authors.lastname: Shaw
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000502:physiology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D009154:Mutation; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D016056:Immunodominant Epitopes; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase