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

      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.


      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, wk12, and after treatment.


      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.


      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.


      Linked Article

      • Direct-acting antivirals trump interferon-alpha in their capacity to rescue exhausted T cells upon HCV clearance
        Journal of HepatologyVol. 61Issue 3
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          The treatment of HCV has been transformed by the capacity of direct acting antivirals (DAAs) to eliminate the infection by attacking the virus effectively. In this issue Martin et al. reveal that these drugs can also harness the immune system by releasing it from the burden of chronic antigen load [1]. Their important findings underscore a detrimental immunoregulatory component to the effects of interferon-alpha (IFN-α), which was not able to boost antiviral T cells in the manner now demonstrated with DAAs, even when it achieved viral clearance (Fig.
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