TY - JOUR
T1 - Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution
AU - Neumann-Haefelin, Christoph
AU - McKiernan, Susan
AU - Ward, Scott
AU - Viazov, Sergei
AU - Spangenberg, Hans Christian
AU - Killinger, Thomas
AU - Baumert, Thomas F.
AU - Nazarova, Natalja
AU - Sheridan, Isabelle
AU - Pybus, Oliver
AU - Von Weizsäcker, Fritz
AU - Roggendorf, Michael
AU - Kelleher, Dermot
AU - Klenerman, Paul
AU - Blum, Hubert E.
AU - Thimme, Robert
PY - 2006/3
Y1 - 2006/3
N2 - Virus-specific CD8+ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8+ T cell responses in determining clinical outcome has not been fully defined. A well-defined cohort of women inoculated with HCV from a single source showed that HLA-B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA-B27 restricted hepatitis C virus (HCV) -specific CD8+ T cell epitope that is recognized in the majority of recovered HLA-B27 positive women. In chronically HCV-infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27, indicating allele-specific selection pressure at the population level. Functional analysis in 3 chronically HCV-infected patients showed that the emerging variant viral epitopes represent escape mutations. In conclusion, our results suggest a dominant role of HLA-B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+ T cell epitope. These results support the central role of virus-specific CD8+ T cells and the genetically determined restriction of the virus-specific T cell repertoire in HCV infection.
AB - Virus-specific CD8+ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8+ T cell responses in determining clinical outcome has not been fully defined. A well-defined cohort of women inoculated with HCV from a single source showed that HLA-B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA-B27 restricted hepatitis C virus (HCV) -specific CD8+ T cell epitope that is recognized in the majority of recovered HLA-B27 positive women. In chronically HCV-infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27, indicating allele-specific selection pressure at the population level. Functional analysis in 3 chronically HCV-infected patients showed that the emerging variant viral epitopes represent escape mutations. In conclusion, our results suggest a dominant role of HLA-B27 in mediating spontaneous viral clearance as well as viral evolution in HCV infection and mechanistically link both associations to a dominant novel CD8+ T cell epitope. These results support the central role of virus-specific CD8+ T cells and the genetically determined restriction of the virus-specific T cell repertoire in HCV infection.
UR - http://www.scopus.com/inward/record.url?scp=33645229492&partnerID=8YFLogxK
U2 - 10.1002/hep.21049
DO - 10.1002/hep.21049
M3 - Article
C2 - 16496339
AN - SCOPUS:33645229492
SN - 0270-9139
VL - 43
SP - 563
EP - 572
JO - Hepatology
JF - Hepatology
IS - 3
ER -
