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HCV genotype-3a T cell immunity: specificity, function and impact of therapy
  1. Isla S Humphreys1,
  2. Annette von Delft1,
  3. Anthony Brown1,
  4. Linda Hibbert2,
  5. Jane D Collier3,
  6. Graham R Foster2,
  7. Monira Rahman1,3,
  8. Annabel Christian3,
  9. Paul Klenerman1,4,
  10. Eleanor Barnes1,4
  1. 1The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
  2. 2Queen Marys, University of London, Institute of Cell and Molecular Sciences, The Liver Unit, London, UK
  3. 3John Radcliffe Hospital, Oxford, UK
  4. 4NIHR Oxford Biomedical Research Centre, Oxford, UK
  1. Correspondence to Dr Eleanor Barnes, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK; ellie.barnes{at}ndm.ox.ac.uk

Abstract

Background Hepatitis C virus (HCV) genotype-3a infection is now the dominant strain in South Asia and the UK. Characteristic features include a favourable response to therapy; the reasons for this are unknown but may include distinct genotype-3a-specific T cell immunity. In contrast to genotype-1 infection, T cell immunity to this subtype is poorly defined.

Objectives The aims of the study were to (1) define the frequency, specificity and cross-reactivity of T cell immunity across the whole viral genome in genotype-3a infection and (2) assess the impact of interferon (IFN)-α/ribavirin on T cell immunity.

Design T cell responses in chronic and resolved HCV genotype-3a were analysed in comparison with genotype-1 infection (total n=85) using specific peptide panels in IFN-γ ELISpot assays. T cell responses were followed longitudinally in a subset of genotype-3a infected patients receiving therapy. Responses were further defined by CD4 and CD8 subset analysis, sequencing of autologous virus and cross-reactivity of genotype-3a with genotype-1a/-1b antigens.

Results CD8 T cell responses commonly targeted the non-structural (NS) proteins in chronic genotype-3a infection whereas in genotype-1 infection CD4 responses targeting HCV core predominated (p=0.0183). Resolved infection was associated with CD4 T cells targeting NS proteins. Paradoxically, a sustained response to therapy was associated with a brisk decline in virus-specific and total lymphocyte counts that recovered after treatment.

Conclusion HCV genotype-3a exhibits a distinct T cell specificity with implications for vaccine design. However, our data do not support the theory that genotype-3a viral clearance with therapy is associated with an enhanced antiviral T cell response. Paradoxically, a reduction in these responses may serve as a biomarker of IFN responsiveness.

  • Hepatitis C virus
  • genotype-3a
  • T cell
  • adaptive immunity
  • interferon
  • ribavirin

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Footnotes

  • IH and AvD contributed equally to the paper.

  • Funding EB was supported by Grant 108/601. EB, IH and AvD are funded by the MRC (UK). PK is funded by the Wellcome trust (UK), the Oxford Martin School and the NIAID U19 Bio-defense Programme (NIH NIAID 1U19AI082630-01). AC is supported by the OXNIHR BRC.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was given by OxRec A.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We are happy to share our raw anonymised data after publication with interested parties.

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