Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection
✍ Scribed by Michael J. Fuller; Naglaa H. Shoukry; Toshifumi Gushima; David G. Bowen; Benoit Callendret; Katherine J. Campbell; Dana L. Hasselschwert; Austin L. Hughes; Christopher M. Walker
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 926 KB
- Volume
- 51
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 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.