The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design

Gut. 2016 Jan;65(1):112-23. doi: 10.1136/gutjnl-2014-308724. Epub 2015 Jun 19.

Abstract

Objective: Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity.

Design: T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed.

Results: In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1.

Conclusions: HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.

Keywords: CELLULAR IMMUNITY; GENOTYPE; HCV.

Publication types

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

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cross Reactions
  • Genotype*
  • Hepacivirus / genetics*
  • Hepacivirus / immunology
  • Hepatitis C / immunology
  • Hepatitis C / virology*
  • Hepatitis C Antigens / genetics
  • Hepatitis C Antigens / immunology*
  • Humans
  • T-Cell Antigen Receptor Specificity / genetics*
  • T-Cell Antigen Receptor Specificity / immunology
  • Viral Hepatitis Vaccines
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / immunology

Substances

  • Hepatitis C Antigens
  • Viral Hepatitis Vaccines
  • Viral Nonstructural Proteins