title: HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope.
abstract: OBJECTIVE
  HLA-B*27 is associated with spontaneous HCV genotype 1 clearance. HLA-B*27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B*27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B*27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope.
  
  
  METHODS
  Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B*27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B*27:02 and 05.
  
  
  RESULTS
  The NS5B2820 epitope is only restricted by the HLA-B*27 subtype HLA-B*27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B*27 subtype B*27:05. Indeed, the epitope is very dominant in HLA-B*27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B*27:02+ chronically infected patients.
  
  
  CONCLUSIONS
  The NS5B2820 epitope is immunodominant in the context of HLA-B*27:02, but is not restricted by other HLA-B*27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.
authors: Department of Medicine II, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors: Katja
authors: K
authors: Nitschke
authors: Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors: Alejandro
authors: A
authors: Barriga
authors: Department of Medicine II, University of Freiburg, Freiburg, Germany.
authors: Julia
authors: J
authors: Schmidt
authors: Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors: Jörg
authors: J
authors: Timm
authors: Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany.
authors: Sergei
authors: S
authors: Viazov
authors: Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA.
authors: Thomas
authors: T
authors: Kuntzen
authors: Division of Infectious Diseases, MGH, Boston, MA, USA.
authors: Arthur Y
authors: AY
authors: Kim
authors: Division of Infectious Diseases, MGH, Boston, MA, USA.
authors: Georg M
authors: GM
authors: Lauer
authors: Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA.
authors: Todd M
authors: TM
authors: Allen
authors: School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Australia; Institute of Immunology and Infectious Disease, Murdoch University, Perth, Western Australia, Australia.
authors: Silvana
authors: S
authors: Gaudieri
authors: Department of Infectious Diseases, Bern University Hospital and University of Bern, Switzerland.
authors: Andri
authors: A
authors: Rauch
authors: Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
authors: Christian M
authors: CM
authors: Lange
authors: Department of Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
authors: Christoph
authors: C
authors: Sarrazin
authors: Transfusion Medicine, HLA-Laboratory, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors: Thomas
authors: T
authors: Eiermann
authors: La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
authors: John
authors: J
authors: Sidney
authors: La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
authors: Alessandro
authors: A
authors: Sette
authors: Department of Medicine II, University of Freiburg, Freiburg, Germany.
authors: Robert
authors: R
authors: Thimme
authors: Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
authors: Daniel
authors: D
authors: López
authors: Department of Medicine II, University of Freiburg, Freiburg, Germany. Electronic address: christoph.neumann-haefelin@uniklinik-freiburg.de.
authors: Christoph
authors: C
authors: Neumann-Haefelin
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000145:classification / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: B-LCL; B-lymphoblastoid cell lines; CD8+ T cell response; EBV; Epstein Barr virus; HCV; HLA; HLA subtypes; HLA-B(⁎)27; HLA-B27; Hepatitis C virus; IFN-γ; NS5B; PBMC; Vaccine design; hepatitis C virus; human leukocyte antigen; interferon-gamma; non-structural protein 5B; peripheral blood mononuclear cell
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