Protective effect of human leukocyte antigen B27 in hepatitis C virus infection requires the presence of a genotype-specific immunodominant CD8+ T-cell epitope.
Human leukocyte antigen B27 (HLA-B27) is associated with protection in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. This protective role is linked to single immunodominant HLA-B27-restricted CD8+ T-cell epitopes in both infections. In order to define the relative contribution of a specific HLA-B27-restricted epitope to the natural course of HCV infection, we compared the biological impact of the highly conserved HCV genotype 1 epitope, for which the protective role has been described, with the corresponding region in genotype 3 that differs in its sequence by three amino acid residues. The genotype 3a peptide was not recognized by CD8+ T cells specific for the genotype 1 peptide. Furthermore, patients with acute or chronic infection with HCV genotype 3a did not mount T-cell responses to this epitope region, and their autologous viral sequences showed no evidence of T-cell pressure. Finally, we found a significantly higher frequency of HLA-B27 positivity in patients with chronic HCV genotype 3a infection compared to genotype 1 infection, indicating that there is no protection by HLA-B27 in HCV genotype 3 infection.


CONCLUSIONS
Our data indicate that the protective effect of HLA-B27 is limited to HCV genotype 1 infection and does not expand to other genotypes such as genotype 3a. This can most likely be explained by intergenotype sequence diversity leading to the loss of the immunodominant HLA-B27 epitope in viral strains other than genotype 1. Our results underline the central role of a single HLA-B27-restricted epitope-specific CD8+ T-cell response in mediating protection in HCV genotype 1 infection.
Neumann-Haefelin
Christoph
C
Department of Medicine II, University of Freiburg, Germany.|Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Germany.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Timm
Jörg
J
Department of Virology, University of Essen, Germany.
Schmidt
Julia
J
Department of Medicine II, University of Freiburg, Germany.|Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Germany.|Faculty of Biology, University of Freiburg, Germany.
Kersting
Nadine
N
Department of Medicine II, University of Freiburg, Germany.
Fitzmaurice
Karen
K
Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland.
Oniangue-Ndza
Cesar
C
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Kemper
Michael N
MN
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Humphreys
Isla
I
Nuffield Department of Clinical Medicine, University of Oxford, UK.
McKiernan
Susan
S
Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland.
Kelleher
Dermot
D
Trinity Centre for Health Sciences, St. James' Hospital, Dublin, Ireland.
Lohmann
Volker
V
Department of Molecular Virology, University of Heidelberg, Germany.
Bowness
Paul
P
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
Huzly
Daniela
D
Department of Virology, University of Freiburg, Germany.
Rosen
Hugo R
HR
Department of Medicine, University of Colorado Health Sciences, Denver, CO.
Kim
Arthur Y
AY
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Lauer
Georg M
GM
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Allen
Todd M
TM
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA.
Barnes
Eleanor
E
Nuffield Department of Clinical Medicine, University of Oxford, UK.
Roggendorf
Michael
M
Department of Virology, University of Essen, Germany.
Blum
Hubert E
HE
Department of Medicine II, University of Freiburg, Germany.
Thimme
Robert
R
Department of Medicine II, University of Freiburg, Germany.
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015796:HLA-B27 Antigen / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen; D016056:Immunodominant Epitopes