title: Restoration of HCV-specific CD8+ T cell function by interferon-free therapy.
abstract: OBJECTIVE
  Chronic hepatitis C virus (HCV) infection is characterised by a failure of virus-specific CD8+ T cells that is mainly caused by viral escape and T cell exhaustion. Constant antigen stimulation has been suggested to contribute to HCV-specific CD8+ T cell exhaustion. However, IFN-based therapies failed to recover HCV-specific CD8+ T cell function suggesting that the damage to CD8+ T cells may be permanent even after antigen removal. It was therefore the objective of this study to analyse the impact of inhibition of ongoing viral replication by IFN-free therapy with direct acting antivirals (DAA) on the phenotype and function of HCV-specific CD8+ T cells.
  
  
  METHODS
  Virus-specific CD8+ T cells obtained from a patient cohort of 51 previously untreated chronically infected patients undergoing IFN-free therapy with a combination of faldaprevir (a protease inhibitor) and deleobuvir (a non-nucleoside polymerase inhibitor) with or without ribavirin were analysed ex vivo and after in vitro expansion at baseline, wk4, wk 12, and after treatment.
  
  
  RESULTS
  Our results show the rapid restoration of proliferative HCV-specific CD8+ T cells in the majority of patients with SVR12 within 4 weeks of therapy suggesting that IFN-free therapy mediated antigen removal may restore CD8+ T cell function.
  
  
  CONCLUSIONS
  This study indicates a specific restoration of proliferative HCV-specific CD8+ T cells under IFN-free therapy. This is in contrast to PegIFN-based therapies that have been shown not to restore T cell function during and after chronic infection.
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Martin
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hennecke
authors.affiliation: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Antonin
authors.initials: A
authors.lastname: Kayser
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.affiliation: Boehringer Ingelheim Canada, Laval, Quebec, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.affiliation: Boehringer Ingelheim Pharma, Ingelheim, Germany.
authors.forename: Wulf-Otto
authors.initials: WO
authors.lastname: Böcher
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany. Electronic address: robert.thimme@uniklinik-freiburg.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D000179:Acrylates / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000075202:Contraindications; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D011092:Polyethylene Glycols; D011392:Proline / Q000031:analogs & derivatives; D011804:Quinolines; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D000179:Acrylates; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D001562:Benzimidazoles; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009842:Oligopeptides; D011804:Quinolines; D011994:Recombinant Proteins; D013844:Thiazoles; D011092:Polyethylene Glycols; D012254:Ribavirin; C000592437:deleobuvir; C552340:faldaprevir; D011392:Proline; C417083:peginterferon alfa-2b; D007930:Leucine; C100416:peginterferon alfa-2a
keywords: Antiviral therapy; DAA; Hepatitis C virus; Immune response; T cell exhaustion; T cell restoration