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
- T cell
- adaptive immunity
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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.