title: Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection.
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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fuller
authors.forename: Naglaa H
authors.initials: NH
authors.lastname: Shoukry
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Gushima
authors.forename: David G
authors.initials: DG
authors.lastname: Bowen
authors.forename: Benoit
authors.initials: B
authors.lastname: Callendret
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Campbell
authors.forename: Dana L
authors.initials: DL
authors.lastname: Hasselschwert
authors.forename: Austin L
authors.initials: AL
authors.lastname: Hughes
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005802:Genes, MHC Class II / Q000235:genetics; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology / Q000821:virology*; D057131:Immune Evasion; D009154:Mutation; D002679:Pan troglodytes
chemical_list: D000939:Epitopes