Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection

Authors

  • Michael J. Fuller,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Naglaa H. Shoukry,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
    Current affiliation:
    1. Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Département de Médecine, Université de Montréal, Montréal, QC, Canada
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  • Toshifumi Gushima,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • David G. Bowen,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
    Current affiliation:
    1. A. W. Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia
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  • Benoit Callendret,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Katherine J. Campbell,

    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Dana L. Hasselschwert,

    1. University of Louisiana at Lafayette New Iberia Research Center, New Iberia, LA
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  • Austin L. Hughes,

    1. Division of Biological Sciences, University of South Carolina, Columbia, SC
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  • Christopher M. Walker

    Corresponding author
    1. Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH
    2. College of Medicine and Public Health, The Ohio State University, Columbus, OH
    • Center for Vaccines and Immunity, WA4011 Research II, The Research Institute at Nationwide Children's Hospital, 700 Childrens Drive, Columbus, OH 43205===

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    • fax: 614-722-3680


  • Potential conflict of interest: Nothing to report.

Abstract

Immune escape driven by selection pressure from virus-specific CD8 T cells has been demonstrated in both chimpanzees and humans infected with the hepatitis C virus (HCV). Although escape mutations have also been characterized in major histocompatibility complex (MHC) class II–restricted HCV epitopes, it is unknown whether selection-driven immune escape by CD4 T cell epitopes is a significant factor in the failure of these responses or contributes to persistent infection. To address this issue, evolution of MHC class I– and class II–restricted HCV epitopes was compared in four chimpanzees persistently infected with the virus for more than 10 years. We identified an amino acid change in a CD4 epitope of the HCV NS3 protein in one of the chimpanzees 3 years after infection. This mutation resulted in diminished activation, cytokine production (interferon-γ and interleukin-2), and proliferation by an epitope-specific CD4 T cell line. We expanded our analysis to determine if mutations were common in multiple CD4 versus CD8 T cell epitopes in the four chronically infected animals. Whereas we observed mutations in over 75% of CD8 T cell epitopes analyzed in this study, only 18% of CD4 T cell epitopes analyzed showed amino acid changes. The frequency of changes in class II epitopes was not different from flanking regions, so CD4 T cells rarely exert selection pressure against the HCV genome. Conclusion: Apparent mutational escape can occur in MHC class II–restricted epitopes, but this is uncommon when compared with class I–restricted epitopes in the same individual. This indicates that other mechanisms for silencing CD4 T cells are dominant in persistent HCV infections. (HEPATOLOGY 2009.)

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