HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope

J Hepatol. 2014 Jan;60(1):22-9. doi: 10.1016/j.jhep.2013.08.009. Epub 2013 Aug 23.

Abstract

Background & aims: HLA-B*27 is associated with spontaneous HCV genotype 1 clearance. HLA-B*27-restricted CD8+ T cells target three NS5B epitopes. Two of these epitopes are dominantly targeted in the majority of HLA-B*27+ patients. In chronic infection, viral escape occurs consistently in these two epitopes. The third epitope (NS5B2820) was dominantly targeted in an acutely infected patient. This was in contrast, however, to the lack of recognition and viral escape in the large majority of HLA-B*27+ patients. Here, we set out to determine the host factors contributing to selective targeting of this epitope.

Methods: Four-digit HLA class I typing and viral sequence analyses were performed in 78 HLA-B*27+ patients with chronic HCV genotype 1 infection. CD8+ T cell analyses were performed in a subset of patients. In addition, HLA/peptide affinity was compared for HLA-B*27:02 and 05.

Results: The NS5B2820 epitope is only restricted by the HLA-B*27 subtype HLA-B*27:02 (that is frequent in Mediterranean populations), but not by the prototype HLA-B*27 subtype B*27:05. Indeed, the epitope is very dominant in HLA-B*27:02+ patients and is associated with viral escape mutations at the anchor position for HLA-binding in 12 out of 13 HLA-B*27:02+ chronically infected patients.

Conclusions: The NS5B2820 epitope is immunodominant in the context of HLA-B*27:02, but is not restricted by other HLA-B*27 subtypes. This finding suggests an important role of HLA subtypes in the restriction of HCV-specific CD8+ responses. With minor HLA subtypes covering up to 39% of specific populations, these findings may have important implications for the selection of epitopes for global vaccines.

Keywords: B-LCL; B-lymphoblastoid cell lines; CD8+ T cell response; EBV; Epstein Barr virus; HCV; HLA; HLA subtypes; HLA-B(⁎)27; HLA-B27; Hepatitis C virus; IFN-γ; NS5B; PBMC; Vaccine design; hepatitis C virus; human leukocyte antigen; interferon-gamma; non-structural protein 5B; peripheral blood mononuclear cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • HLA-B27 Antigen / classification
  • HLA-B27 Antigen / immunology*
  • Hepacivirus / immunology*
  • Humans
  • Viral Nonstructural Proteins / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA-B27 Antigen
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins