Naturally occurring CD4+ T-cell epitope variants act as altered peptide ligands leading to impaired helper T-cell responses in hepatitis C virus infection

Matthew F. Cusick, Meiying Yang, Joan C. Gill, David D. Eckels*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Hepatitis C virus (HCV) has a high rate of replication and lacks RNA-proofreading capabilities, thereby leading to variant or mutant viruses circulating within the host as a quasispecies. Previous work in our laboratory identified viral variants that emerged in a class-II immunodominant epitope NS3358-375 of the non-structural-3 (NS3) protein region of HCV, the sequence of which is based on genotype 1A, the most prevalent genotype in the United States. Further work suggested that positive immune selection pressure was driving viral variation. Paradoxically, viral variants account for only a small percentage of the circulating virus in human beings and in chimpanzees, suggesting that passive evasion is not the only means of escape by HCV. This observation suggests a unique pathogenesis for HCV as it persists in the host. In the current study, we hypothesize that viral variants are acting as altered peptide ligands (APLs). To test this hypothesis, we used cloned T cells specific for NS3358-375 peptide, which demonstrated attenuated T-cell and interferon-γ (IFN-γ) responses to individual variant peptides, when compared with the NS3358-375 stimulated T-cell clones. Furthermore, such variants could act as APLs, based on their ability to antagonize the IFN-γ proliferative responses of clones specific for NS3358-375. In addition, major histocompatibility complex (MHC) class II tetramer staining demonstrated that variant peptide-MHC complexes were able to specifically bind to NS3358-375 T-cell clones and that both the variant and NS3358-375 tetramers were able to bind to the same CD4+ T cells. Taken together, the results suggest that viral variants may act as APL to effectively blunt the T-cell response to an important HCV epitope.

Original languageEnglish (US)
Pages (from-to)379-385
Number of pages7
JournalHuman Immunology
Issue number5
StatePublished - May 2011


  • Altered peptide ligands
  • Antagonism
  • Hepatitis C virus
  • Human CD4 T cells
  • MHC class II tetramer

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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