Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics

Gastroenterology. 2006 Dec;131(6):1887-98. doi: 10.1053/j.gastro.2006.09.052. Epub 2006 Oct 1.

Abstract

Background & aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Current therapy with pegylated interferon alpha (IFN-alpha) in combination with ribavirin is associated with adverse effects and often fails to induce a sustained response. IFN-lambdas, recently discovered IFN gene family members, exhibit antiviral and cell stimulatory activities similar to IFN-alpha. We aimed to determine whether IFN-lambda exhibits antiviral activity toward HCV and to compare the signal transduction and effector gene pathways with those of IFN-alpha.

Methods: Using the HCV replicon system and cell culture infectious reporter virus, we compared IFN-alpha and IFN-lambda effects on HCV RNA replication and protein expression, as measured by quantitative reverse-transcriptase polymerase chain reaction, luciferase expression, and Western blot. Receptor expression and signaling pathways were explored using flow cytometry and Western blot. IFN-alpha- and IFN-lambda-mediated gene expression changes were compared using microarray analyses.

Results: IFN-lambda exhibited dose- and time-dependent HCV inhibition, independent of types I and II IFN receptors. The kinetics of IFN-lambda-mediated signal transducers and activators of transcription (STAT) activation and induction of potential effector genes were distinct from those of IFN-alpha. IFN-lambda induced steady increases in levels of known interferon stimulated genes (ISGs), whereas IFN-alpha ISGs peaked early and declined rapidly. IFN-lambda inhibited replication of HCV genotypes 1 and 2 and enhanced the antiviral efficacy of subsaturating levels of IFN-alpha.

Conclusions: These results demonstrate distinct differences in IFN-lambda- and IFN-alpha-induced antiviral states. Understanding these differences may prove useful for developing new HCV treatment strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / virology
  • Cell Line, Tumor
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Viral / drug effects*
  • Hepacivirus / genetics*
  • Humans
  • Interferon-alpha / pharmacology*
  • Interferons
  • Interleukins / pharmacology*
  • Liver Neoplasms / pathology
  • Liver Neoplasms / virology
  • Oligonucleotide Array Sequence Analysis
  • RNA, Viral / genetics
  • Signal Transduction / drug effects*
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Cytokines
  • IFNL1 protein, human
  • Interferon-alpha
  • Interleukins
  • RNA, Viral
  • Interferons