IL-28B (IFN-λ3) and IFN-α synergistically inhibit HCV replication

J Viral Hepat. 2013 Apr;20(4):281-9. doi: 10.1111/j.1365-2893.2012.01649.x. Epub 2012 Aug 7.

Abstract

Genetic variation in the IL-28B (interleukin-28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon-α and ribavirin. However, the mechanisms by which polymorphisms in the IL-28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN-λs and IFN-α on HCV RNA replication. The anti-HCV effect of IFN-λ3 and IFN-α in combination was also assessed. Changes in gene expression induced by IFN-λ3 and IFN-α were compared using cDNA microarray analysis. IFN-λs at concentrations of 1 ng/mL or more exhibited concentration- and time-dependent HCV inhibition. In combination, IFN-λ3 and IFN-α had a synergistic anti-HCV effect; however, no synergistic enhancement was observed for interferon-stimulated response element (ISRE) activity or upregulation of interferon-stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN-λ3-induced gene expression occurred later and lasted longer than that induced by IFN-α. In addition, although the genes upregulated by IFN-α and IFN-λ3 were similar to microarray analysis, interferon-stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN-α and IFN-λ3 in combination showed synergistic anti-HCV activity in vitro. Differences in time-dependent upregulation of these genes might contribute to the synergistic antiviral activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Biological Products / pharmacology*
  • Cell Line
  • Drug Synergism
  • Gene Expression Profiling
  • Hepacivirus / drug effects*
  • Hepacivirus / physiology*
  • Hepatocytes / immunology
  • Hepatocytes / virology
  • Humans
  • Interferon-alpha / pharmacology*
  • Interferons
  • Interleukins / pharmacology*
  • Microarray Analysis
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Biological Products
  • IFNL3 protein, human
  • Interferon-alpha
  • Interleukins
  • Interferons