Restoration of HCV-specific CD8+ T cell function by interferon-free therapy

J Hepatol. 2014 Sep;61(3):538-43. doi: 10.1016/j.jhep.2014.05.043. Epub 2014 Jun 4.


Background & aims: 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.

Keywords: Antiviral therapy; DAA; Hepatitis C virus; Immune response; T cell exhaustion; T cell restoration.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylates / pharmacology
  • Acrylates / therapeutic use
  • Adult
  • Aged
  • Aminoisobutyric Acids
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use*
  • Benzimidazoles / pharmacology
  • Benzimidazoles / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Contraindications
  • Drug Therapy, Combination
  • Female
  • Hepacivirus* / drug effects
  • Hepacivirus* / physiology
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / pathology
  • Humans
  • In Vitro Techniques
  • Interferon alpha-2
  • Interferon-alpha
  • Leucine / analogs & derivatives
  • Male
  • Middle Aged
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Polyethylene Glycols
  • Proline / analogs & derivatives
  • Quinolines
  • Recombinant Proteins
  • Ribavirin / pharmacology
  • Ribavirin / therapeutic use
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use
  • Treatment Outcome
  • Virus Replication / drug effects
  • Virus Replication / physiology


  • Acrylates
  • Aminoisobutyric Acids
  • Antiviral Agents
  • Benzimidazoles
  • Interferon alpha-2
  • Interferon-alpha
  • Oligopeptides
  • Quinolines
  • Recombinant Proteins
  • Thiazoles
  • Polyethylene Glycols
  • Ribavirin
  • deleobuvir
  • faldaprevir
  • Proline
  • peginterferon alfa-2b
  • Leucine
  • peginterferon alfa-2a