title: HCV genotype-3a T cell immunity: specificity, function and impact of therapy.
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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, UK.
authors.forename: Isla S
authors.initials: IS
authors.lastname: Humphreys
authors.forename: Annette
authors.initials: A
authors.lastname: von Delft
authors.forename: Anthony
authors.initials: A
authors.lastname: Brown
authors.forename: Linda
authors.initials: L
authors.lastname: Hibbert
authors.forename: Jane D
authors.initials: JD
authors.lastname: Collier
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
authors.forename: Monira
authors.initials: M
authors.lastname: Rahman
authors.forename: Annabel
authors.initials: A
authors.lastname: Christian
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000627:therapeutic use; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D012016:Reference Values; D012254:Ribavirin / Q000627:therapeutic use; D012680:Sensitivity and Specificity; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D007371:Interferon-gamma