title: Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations.
abstract: Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8(+) T-cell epitope, nonstructural protein (NS)5B(2841-2849) (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B(2936-2944) (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a-infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27(+) subjects, rare escape mutations arose at the HLA-B27 anchor residue, R(2937) , which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from <5% to ≥ 70% of wild-type levels.
  
  
  CONCLUSIONS
  The selection of rare CTL escape mutations in this HLA-B27-restricted epitope dramatically impairs viral replicative fitness, unless properly compensated. These data support a role for the targeting of highly constrained regions by HLA-B27 in its ability to assert immune control of HCV and other highly variable pathogens.
authors: Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA.
authors: Christoph
authors: C
authors: Neumann-Haefelin
authors: Cesar
authors: C
authors: Oniangue-Ndza
authors: Thomas
authors: T
authors: Kuntzen
authors: Julia
authors: J
authors: Schmidt
authors: Katja
authors: K
authors: Nitschke
authors: John
authors: J
authors: Sidney
authors: Célia
authors: C
authors: Caillet-Saguy
authors: Marco
authors: M
authors: Binder
authors: Nadine
authors: N
authors: Kersting
authors: Michael W
authors: MW
authors: Kemper
authors: Karen A
authors: KA
authors: Power
authors: Susan
authors: S
authors: Ingber
authors: Laura L
authors: LL
authors: Reyor
authors: Kelsey
authors: K
authors: Hills-Evans
authors: Arthur Y
authors: AY
authors: Kim
authors: Georg M
authors: GM
authors: Lauer
authors: Volker
authors: V
authors: Lohmann
authors: Alessandro
authors: A
authors: Sette
authors: Matthew R
authors: MR
authors: Henn
authors: Stéphane
authors: S
authors: Bressanelli
authors: Robert
authors: R
authors: Thimme
authors: Todd M
authors: TM
authors: Allen
mesh_terms: D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015796:HLA-B27 Antigen / Q000235:genetics* / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D014779:Virus Replication / Q000235:genetics* / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D016056:Immunodominant Epitopes