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

A. Von Delft, I.S. Humphreys, A. Brown, K. Pfafferott, Michaela Lucas, P. Klenerman, G.M. Lauer, A.L. Cox, Silvana Gaudieri, E. Barnes

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    Abstract

    © 2016, BMJ Publishing Group. All rights reserved. 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
    Pages (from-to)112-123
    JournalGut
    Volume65
    Issue number1
    DOIs
    Publication statusPublished - 2016

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    Vaccines
    Genotype
    T-Lymphocytes
    HLA Antigens
    Infection
    Epitopes
    Chronic Disease
    T-Cell Antigen Receptor Specificity
    Peptides
    T-Lymphocyte Subsets
    Proteins

    Cite this

    Von Delft, A. ; Humphreys, I.S. ; Brown, A. ; Pfafferott, K. ; Lucas, Michaela ; Klenerman, P. ; Lauer, G.M. ; Cox, A.L. ; Gaudieri, Silvana ; Barnes, E. / The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design. In: Gut. 2016 ; Vol. 65, No. 1. pp. 112-123.
    @article{fb53c119683d4dfeacf78c7a65c7af20,
    title = "The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design",
    abstract = "{\circledC} 2016, BMJ Publishing Group. All rights reserved. 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.",
    author = "{Von Delft}, A. and I.S. Humphreys and A. Brown and K. Pfafferott and Michaela Lucas and P. Klenerman and G.M. Lauer and A.L. Cox and Silvana Gaudieri and E. Barnes",
    year = "2016",
    doi = "10.1136/gutjnl-2014-308724",
    language = "English",
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    Von Delft, A, Humphreys, IS, Brown, A, Pfafferott, K, Lucas, M, Klenerman, P, Lauer, GM, Cox, AL, 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, vol. 65, no. 1, pp. 112-123. https://doi.org/10.1136/gutjnl-2014-308724

    The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design. / Von Delft, A.; Humphreys, I.S.; Brown, A.; Pfafferott, K.; Lucas, Michaela; Klenerman, P.; Lauer, G.M.; Cox, A.L.; Gaudieri, Silvana; Barnes, E.

    In: Gut, Vol. 65, No. 1, 2016, p. 112-123.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design

    AU - Von Delft, A.

    AU - Humphreys, I.S.

    AU - Brown, A.

    AU - Pfafferott, K.

    AU - Lucas, Michaela

    AU - Klenerman, P.

    AU - Lauer, G.M.

    AU - Cox, A.L.

    AU - Gaudieri, Silvana

    AU - Barnes, E.

    PY - 2016

    Y1 - 2016

    N2 - © 2016, BMJ Publishing Group. All rights reserved. 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.

    AB - © 2016, BMJ Publishing Group. All rights reserved. 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.

    U2 - 10.1136/gutjnl-2014-308724

    DO - 10.1136/gutjnl-2014-308724

    M3 - Article

    VL - 65

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    EP - 123

    JO - Gut: an international journal of gastroenterology & hepatology

    JF - Gut: an international journal of gastroenterology & hepatology

    SN - 0017-5749

    IS - 1

    ER -