期刊
HEPATOLOGY
卷 51, 期 2, 页码 378-387出版社
WILEY
DOI: 10.1002/hep.23319
关键词
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资金
- Public Health Service [U19A148231]
- American Cancer Society
- National Health and Medical Research Foundation, Australia
- American Liver Foundation
- Canadian Institute for Health Research
- National Institutes of Health [GM43940]
- National Center for Research Resources, National Institutes of Health [C06 RR016483-01]
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-gamma 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 11 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 2010;51:378-387.)
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