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

Annette Von Delft, Isla S. Humphreys, Anthony Brown, Katja Pfafferott, Michaela Lucas, Paul Klenerman, Georg M. Lauer, Andrea L. Cox, Silvana Gaudieri, Eleanor Barnes

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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.

Original languageEnglish (US)
Pages (from-to)112-123
Number of pages12
JournalGut
Volume65
Issue number1
DOIs
StatePublished - Jan 2016

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ASJC Scopus subject areas

  • Gastroenterology

Cite this

Von Delft, A., Humphreys, I. S., Brown, A., Pfafferott, K., Lucas, M., Klenerman, P., Lauer, G. M., Cox, A. L., Gaudieri, S., & Barnes, E. (2016). The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design. Gut, 65(1), 112-123. https://doi.org/10.1136/gutjnl-2014-308724