Targeting lipid metabolism in the treatment of hepatitis C virus infection

J Infect Dis. 2008 Feb 1;197(3):361-70. doi: 10.1086/525287.

Abstract

Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus (HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepatitis C / therapy*
  • Humans
  • Lipids / physiology*
  • Liver Neoplasms
  • Plasmids
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Virus Replication / drug effects

Substances

  • Lipids
  • RNA, Small Interfering
  • phytosphingosine
  • Sphingosine