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: 6).
03/2008; 197(3):361-70. DOI: 10.1086/525287
Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called “lipid rafts”) have been considered
to act as a scaffold for the hepatitisCvirus(HCV)replication complex. Using theHCVcell 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.
Available from: Florian Douam
- "Altogether, these observations reflect the important role of lipids in the HCV life cycle. Therefore, host factors involved in cholesterol/lipid metabolism might represent potential targets for HCV strategies, with only limited possibilities for escape mutations to develop ,  and allowing treatment of patients infected with genotype 3 HCV . "
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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.
Available from: Lisa M Johansen
- "AY-9944 and triparanol, inhibitors of the downstream targets D7-and D24- reductase, respectively, exhibited marginal selectivity despite previous reports that inhibition of these sterol reductases is compatible with cell proliferation (Rujanavech and Silbert, 1986; Fernandez et al, 2005). Previous reports have suggested that viral replication is impacted by the products of the fatty acid biosynthesis pathway (Kapadia and Chisari, 2005; Amemiya et al, 2008). We found that the chemical probe Table I Chemical probes that inhibit enzymes within and outside the sterol pathway "
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ABSTRACT: The search for effective Hepatitis C antiviral therapies has recently focused on host sterol metabolism and protein prenylation pathways that indirectly affect viral replication. However, inhibition of the sterol pathway with statin drugs has not yielded consistent results in patients. Here, we present a combination chemical genetic study to explore how the sterol and protein prenylation pathways work together to affect hepatitis C viral replication in a replicon assay. In addition to finding novel targets affecting viral replication, our data suggest that the viral replication is strongly affected by sterol pathway regulation. There is a marked transition from antagonistic to synergistic antiviral effects as the combination targets shift downstream along the sterol pathway. We also show how pathway regulation frustrates potential hepatitis C therapies based on the sterol pathway, and reveal novel synergies that selectively inhibit hepatitis C replication over host toxicity. In particular, combinations targeting the downstream sterol pathway enzymes produced robust and selective synergistic inhibition of hepatitis C replication. Our findings show how combination chemical genetics can reveal critical pathway connections relevant to viral replication, and can identify potential treatments with an increased therapeutic window. Molecular Systems Biology 6: 375; published online 8 June 2010; doi:10.1038/msb.2010.32
Available from: PubMed Central
- "Currently approved therapies for infections with these pathogens are limited, and the development of specific viral enzyme-targeted inhibitors is frequently complicated by the inherently high mutation rate of viral RNA polymerases and the rapid development of resistance [3,4]. An alternative approach that has been advocated in the development of novel and potential broadly active antivirals is the targeting of host processes, which range from blockade of cell surface receptors to altering cellular metabolism [5–9]. However, the cell-centric approach to antiviral development requires substantial knowledge and understanding of the host-pathogen interactions that control virus replication. "
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ABSTRACT: Positive-sense RNA viruses are responsible for frequent and often devastating diseases in humans, animals, and plants. However, the development of effective vaccines and anti-viral therapies targeted towards these pathogens has been hindered by an incomplete understanding of the molecular mechanisms involved in viral replication. One common feature of all positive-sense RNA viruses is the manipulation of host intracellular membranes for the assembly of functional viral RNA replication complexes. This review will discuss the interplay between cellular membranes and positive-sense RNA virus replication, and will focus specifically on the potential structural and functional roles for cellular lipids in this process.
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