Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution.
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.
Department of Medicine II, University of Freiburg, Germany.
Christoph
C
Neumann-Haefelin
Susan
S
McKiernan
Scott
S
Ward
Sergei
S
Viazov
Hans Christian
HC
Spangenberg
Thomas
T
Killinger
Thomas F
TF
Baumert
Natalja
N
Nazarova
Isabelle
I
Sheridan
Oliver
O
Pybus
Fritz
F
von Weizsäcker
Michael
M
Roggendorf
Dermot
D
Kelleher
Paul
P
Klenerman
Hubert E
HE
Blum
Robert
R
Thimme
D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged
D018984:Epitopes, T-Lymphocyte; D015796:HLA-B27 Antigen