Targeting lipid metabolism in the treatment of hepatitis C virus infection.

First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Chuo, Japan.
The Journal of Infectious Diseases (Impact Factor: 5.78). 03/2008; 197(3):361-70. DOI: 10.1086/525287
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Viruses, despite having small genomes and few proteins, make an array of interactions with host proteins as they solely depend on host machinery for their replication and reproduction. Hence, analysis of the Human-Virus Protein-Protein Interaction Network (Hu-Vir PPI network) helps us to gain certain insights into the molecular mechanisms underlying the hijacking of host cell machinery by viruses for their perpetuation. Here we report an analysis of the Human-Virus Bridged PPI Networks that has led us to identify viral articulation points (VAPs) which connect unconnected components of the Human-PPI (Hu-PPI) network. VAPs cross-link peripheral nodes to the giant component of the Hu-PPI network. VAPs interact with a number of relatively lower topologically central human proteins and are conserved among related viruses. The linked nodes comprise of those that are mostly expressed during viral infection, as well as those that are found exclusively in some metabolic pathways, indicating that the novel viral mediation of certain human protein-protein interactions may form the basis for virus-specific tuning of the host machinery. The functional importance of VAPs and their interaction partners in virus replication make them potential drug targets against viral infection. Our investigations also led to the discovery of an example of a Human Endogenous Retrovirus (HERV) encoded protein, syncytin, as an Articulation Point (AP) in the Hu-PPI network, suggesting that VAPs may be retained in a genome if they result in any beneficial function in the host.
    Molecular BioSystems 07/2014; · 3.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used for the treatment of hypercholesterolemia. Besides their cholesterol-lowering effect, statins have been reported to have antiviral activity against a variety of viruses, including hepatitis C virus (HCV). Several statins inhibit the in vitro replication of subgenomic HCV replicons and also suppress in vitro RNA replication of infectious HCV. The precise mechanism of the anti-HCV activity of statins has not yet been defined. Recent studies suggest that the antiviral effect may result from the inhibition of geranylgeranylation of cellular proteins, rather than the inhibition of cholesterol synthesis. Despite the antiviral effect observed in vitro, statin monotherapy seems to be insufficient for the treatment of chronic HCV infection. However, several prospective and retrospective studies have demonstrated that the addition of statins to IFN-α and ribavirin therapy increases SVR, RVR, and EVR rates without the occurrence of additional adverse events. These clinical data, together with the excellent safety profile and low cost, suggest that statins may play a role in HCV therapy until more potent and safe direct-acting antivirals become available. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”
    Antiviral research 01/2014; · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) establishes infection using host lipid metabolism pathways that are thus considered potential targets for indirect anti-HCV strategies. HCV enters the cell via clathrin-dependent endocytosis, interacting with several receptors, and virus-cell fusion, which depends on acidic pH and the integrity of cholesterol-rich domains of the hepatocyte membrane. The ATP-binding Cassette Transporter A1 (ABCA1) mediates cholesterol efflux from hepatocytes to extracellular Apolipoprotein A1 and moves cholesterol within cell membranes. Furthermore, it generates high-density lipoprotein (HDL) particles. HDL protects against arteriosclerosis and cardiovascular disease. We show that the up-regulation of ABCA1 gene expression and its cholesterol efflux function in Huh7.5 hepatoma cells, using the liver X receptor (LXR) agonist GW3965, impairs HCV infection and decreases levels of virus produced. ABCA1-stimulation inhibited HCV cell entry, acting on virus-host cell fusion, but had no impact on virus attachment, replication, or assembly/secretion. It did not affect infectivity or properties of virus particles produced. Silencing of the ABCA1 gene and reduction of the specific cholesterol efflux function counteracted the inhibitory effect of the GW3965 on HCV infection, providing evidence for a key role of ABCA1 in this process. Impaired virus-cell entry correlated with the reorganisation of cholesterol-rich membrane microdomains (lipid rafts). The inhibitory effect could be reversed by an exogenous cholesterol supply, indicating that restriction of HCV infection was induced by changes of cholesterol content/distribution in membrane regions essential for virus-cell fusion. Stimulation of ABCA1 expression by GW3965 inhibited HCV infection of both human primary hepatocytes and isolated human liver slices. This study reveals that pharmacological stimulation of the ABCA1-dependent cholesterol efflux pathway disrupts membrane cholesterol homeostasis, leading to the inhibition of virus-cell fusion and thus HCV cell entry. Therefore besides other beneficial roles, ABCA1 might represent a potential target for HCV therapy.
    PLoS ONE 01/2014; 9(3):e92140. · 3.53 Impact Factor