Negative Regulation of Hepatitis C Virus Specific Immunity Is Highly Heterogeneous and Modulated by Pegylated interferon-alpha/ribavirin Therapy

PLoS One. 2012;7(11):e49389. doi: 10.1371/journal.pone.0049389. Epub 2012 Nov 8.

Abstract

Specific inhibitory mechanisms suppress the T-cell response against the hepatitis C virus (HCV) in chronically infected patients. However, the relative importance of suppression by IL-10, TGF-β and regulatory T-cells and the impact of pegylated interferon-alpha and ribavirin (PegIFN-α/ribavirin) therapy on these inhibitory mechanisms are still unclear. We revealed that coregulation of the HCV-specific T-cell responses in blood of 43 chronic HCV patients showed a highly heterogeneous pattern before, during and after PegIFN-α/ribavirin. Prior to treatment, IL-10 mediated suppression of HCV-specific IFN-γ production in therapy-naive chronic HCV patients was associated with higher HCV-RNA loads, which suggests that protective antiviral immunity is controlled by IL-10. In addition, as a consequence of PegIFN-α/ribavirin therapy, negative regulation of especially HCV-specific IFN-γ production by TGF-β and IL-10 changed dramatically. Our findings emphasize the importance of negative regulation for the dysfunctional HCV-specific immunity, which should be considered in the design of future immunomodulatory therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antiviral Agents / therapeutic use*
  • Cell Proliferation
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Immunity, Cellular / physiology*
  • Interferon-alpha / therapeutic use*
  • Interleukin-10 / immunology
  • Male
  • Middle Aged
  • RNA, Viral / blood
  • Ribavirin / therapeutic use*
  • T-Lymphocytes, Regulatory / immunology
  • Transforming Growth Factor beta / immunology
  • Virus Replication

Substances

  • Antiviral Agents
  • Interferon-alpha
  • RNA, Viral
  • Transforming Growth Factor beta
  • Interleukin-10
  • Ribavirin

Grant support

This work was funded by the Foundation for Liver and Gastrointestinal Research (SLO), Rotterdam, the Netherlands, and further supported by Schering-Plough now MSD, the Virgo consortium, funded by the Dutch government, project number FES0908, and by the Netherlands Genomics Initiative (NGI), project number 050-060-452. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.