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    Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection.

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    Authors
    Fitzmaurice, Karen
    Petrovic, Danijela
    Ramamurthy, Narayan
    Simmons, Ruth
    Merani, Shazma
    Gaudieri, Silvana
    Sims, Stuart
    Dempsey, Eugene
    Freitas, Elizabeth
    Lea, Susan
    McKiernan, Susan
    Norris, Suzanne
    Long, Aideen
    Kelleher, Dermot
    Klenerman, Paul
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    Affiliation
    Department of Clinical Medicine, Trinity College Dublin, St James' Hospital,, Dublin, Ireland. kfitzmau@tcd.ie
    Issue Date
    2012-02-01T10:45:47Z
    MeSH
    Adult
    Alleles
    CD8-Positive T-Lymphocytes/*immunology
    Cohort Studies
    *DNA Footprinting
    Electroporation
    Epitopes, T-Lymphocyte/chemistry/*immunology
    Female
    Genetic Fitness/immunology
    HLA-A3 Antigen/genetics/*immunology
    Hepatitis C/*immunology
    Humans
    Immunodominant Epitopes/immunology
    Protein Biosynthesis/immunology
    Sequence Alignment
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    Citation
    Gut. 2011 Nov;60(11):1563-71. Epub 2011 May 6.
    Journal
    Gut
    URI
    http://hdl.handle.net/10147/207825
    DOI
    10.1136/gut.2010.228403
    PubMed ID
    21551190
    Abstract
    BACKGROUND AND AIMS: CD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response. METHODS: A sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants. RESULTS: A strong 'HLA footprint' in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03-positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A. CONCLUSIONS: It is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies.
    Language
    eng
    ISSN
    1468-3288 (Electronic)
    0017-5749 (Linking)
    ae974a485f413a2113503eed53cd6c53
    10.1136/gut.2010.228403
    Scopus Count
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