Degree of cross-genotype reactivity of hepatitis C virus-specific CD8+ T cells directed against NS3

Hepatology. 2009 Sep;50(3):707-16. doi: 10.1002/hep.23096.


The inherent sequence diversity of the hepatitis C virus (HCV) with the existence of multiple genotypes that differ up to 20% at the amino acid level represents one of the major obstacles for immune control. Accordingly, immune control of a heterologous virus challenge, particularly across genotypes, is difficult to achieve; however, the overall role of genotype-specific sequence differences has not yet been defined at the epitope level. The aim of this study was to determine the role of genotype-specific sequence differences for the CD8+ T cell response against HCV. We analyzed a cohort of anti-HCV-positive injection drug users infected with HCV genotype 1 (n = 17) or genotype 3 (n = 22) or undetectable HCV-RNA (n = 14) with overlapping peptides covering consensus sequences of NS3 from both genotypes. Importantly, the majority of HCV-specific CD8 T cells were specific for one genotype only indicating that sequence differences between genotypes are relevant at the epitope level. Interestingly, T cells active against both genotypes were significantly more frequent in HCV-RNA-negative subjects. Of note, we identified five subjects with undetectable viremia and coexistence of two T cell populations-one for each genotype-suggesting immune control of two different genotypes.

Conclusion: We systematically analyzed the degree of cross-genotype reactivity of HCV-specific T cells and have shown that CD8 responses targeting different HCV genotypes can be primed in the same individual and that such responses potentially characterize a subgroup among injection drug users being protected from chronic HCV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • Cross Reactions
  • Drug Users
  • Epitopes
  • Female
  • Genotype
  • Hepacivirus / genetics
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Male
  • Middle Aged
  • Viral Nonstructural Proteins / genetics*


  • Epitopes
  • NS3 protein, hepatitis C virus
  • Viral Nonstructural Proteins