Z Gastroenterol 2011; 49 - P4_41
DOI: 10.1055/s-0030-1269696

Protection from persistent hepatitis C virus infection by HLA class I: The need for multiple escape mutations in immunodominant T cell epitopes is a common feature

J Schmidt 1, K Wunsch 1, T Kuntzen 2, C Oniangue-Ndza 2, TM Allen 2, R Thimme 1, C Neumann-Haefelin 1
  • 1Abt. Innere Medizin II, Medizinische Universitätsklinik Freiburg, Freiburg
  • 2Ragon Institute of MGH, MIT and Harvard, Boston, USA

Certain HLA class I alleles are associated with spontaneous resolution of acute hepatitis C virus (HCV) infection. We have recently elucidated the mechanisms of protection by HLA-B27. Viral escape from an immunodominant (Dazert, Neumann-Haefelin et al., J Clin Invest 2009) as well as from a subdominant HLA-B27 restricted HCV-specific CD8+ T cell response (Neumann-Haefelin et al., manuscript submitted) requires the emergence of multiple mutations within a single viral genome, suggesting escape from HLA-B27 restricted CD8+ T cell responses can not occur easily. This may lead to viral clearance rather than viral evolution and persistence. Here, we demonstrate that similar mechanisms also apply to immunodominant CD8+ T cell epitopes restricted by other protective epitopes such as HLA-B39 and B62. Indeed, a viral sequence analyses in a large cohort of genotype 1a infected patients (n=404) led to the identification of two novel immunodominant HLA-B39 and B62 restricted CD8+ T cell epitopes which were confirmed in functional assays. Both epitopes contained two HLA specific sequence polymorphisms. In vitro replication assays revealed that one of these mutations in each epitope has a significant impact on viral replication (viral fitness cost), while escape mutations in control epitopes restricted by non-protective HLA class I alleles were not associated with significant fitness costs. These findings support the notion that protection from chronic HCV infection is mediated by immunodominant CD8+ T cell responses that can not be escaped from easily by HCV. The definition of such protective HCV-specific CD8+ T cell epitopes is an important prerequisite for the development of successful T cell based vaccination strategies.