The influence of cholesterol and lipid metabolism on host cell structure and hepatitis C virus replication

Sagan, Selena M.; Rouleau, Y; Leggiadro, Cynthia; Supeková, Lubica; Schultz, Peter G.; Su, Andrew I.; Pezacki, John Paul

doi:10.1139/o05-149

Cited by 75 publications

(82 citation statements)

References 38 publications

(65 reference statements)

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“…These experiments were performed in cultured cells, and the concentrations of the inhibitor tested did not induce host cell toxicity or apoptosis [6]. Similar results have been obtained for DENV, yellow fever virus (YFV), WNV, and HCV using the FASN inhibitor C75 [9,81,102,119], or cerulenin, another FASN inhibitor [81,102,111]. HMCV, influenza A, DENV, YFV, and WNV are enveloped viruses.…”

Section: Inhibitors Of Fatty Acid Biosynthesis As Potential Antiviralsupporting

confidence: 57%

“…Several studies have highlighted the role of the cholesterol and the cholesterol biosynthetic pathway in the replication of viruses, including important human pathogens belonging to the Flaviviridae family -WNV [90], DENV [110], and HCV [8,[111][112][113] Table 2. Examples of host cell genes associated to lipid metabolism and involved in viral replication associated to the infection of animal pathogens like African swine fever virus [115].…”

Section: Cellular Lipids Involved In Viral Replication Complex Assemblymentioning

confidence: 99%

See 1 more Smart Citation

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Martín-Acebes¹,

Vázquez-Calvo²,

Caridi³

et al. 2013

Lipid Metabolism

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Section: Inhibitors Of Fatty Acid Biosynthesis As Potential Antiviralsupporting

confidence: 57%

Section: Cellular Lipids Involved In Viral Replication Complex Assemblymentioning

confidence: 99%

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Martín-Acebes¹,

Vázquez-Calvo²,

Caridi³

et al. 2013

Lipid Metabolism

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“…Similarly to tombusviruses, the replication of other viruses, such as Dengue virus, Norwalk virus, and hepatitis C virus (HCV), also depends on sterols (6,18,46,47). It has been shown that the HCV replicase complex is associated with cholesterol-rich lipid rafts (2).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Sterol Biosynthesis Reduces Tombusvirus Replication in Yeast and Plants

Sharma

Sasvari

Nagy

2010

J Virol

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The replication of plus-strand RNA viruses depends on subcellular membranes. Recent genome-wide screens have revealed that the sterol biosynthesis genes ERG25 and ERG4 affected the replication of Tomato bushy stunt virus (TBSV) in a yeast model host. To further our understanding of the role of sterols in TBSV replication, we demonstrate that the downregulation of ERG25 or the inhibition of the activity of Erg25p with an inhibitor (6-amino-2-n-pentylthiobenzothiazole; APB) leads to a 3-to 5-fold reduction in TBSV replication in yeast. In addition, the sterol biosynthesis inhibitor lovastatin reduced TBSV replication by 4-fold, confirming the importance of sterols in viral replication. We also show reduced stability for the p92 pol viral replication protein as well as a decrease in the in vitro activity of the tombusvirus replicase when isolated from APB-treated yeast. Moreover, APB treatment inhibits TBSV RNA accumulation in plant protoplasts and in Nicotiana benthamiana leaves. The inhibitory effect of APB on TBSV replication can be complemented by exogenous stigmasterol, the main plant sterol, suggesting that sterols are required for TBSV replication. The silencing of SMO1 and SMO2 genes, which are orthologs of ERG25, in N. benthamiana reduced TBSV RNA accumulation but had a lesser inhibitory effect on the unrelated Tobacco mosaic virus, suggesting that various viruses show different levels of dependence on sterol biosynthesis for their replication.Plus-stranded RNA [(ϩ)RNA] viruses usurp various intracellular/organellar membranes for their replication. These cellular membranes are thought to facilitate the building of viral factories, promote a high concentration of membrane-bound viral proteins, and provide protection against cellular nucleases and proteases (1,12,35,44). The membrane lipids and proteins may serve as scaffolds for targeting the viral replication proteins or for the assembly of the viral replicase complex. The subcellular membrane also may provide critical lipid or protein cofactors to activate/modulate the function of the viral replicase. Indeed, the formation of spherules, consisting of lipid membranes bended inward and viral replication proteins as well as recruited host proteins, has been demonstrated for several (ϩ)RNA viruses (20,30,48). These virus-induced spherules serve as sites of viral replication. Importantly, (ϩ)RNA viruses also induce membrane proliferation that requires new lipid biosynthesis. Therefore, it is not surprising that several genome-wide screens for the identification of host factors affecting (ϩ)RNA virus replication unraveled lipid biosynthesis/metabolism genes (8,23,38,50). However, in spite of these intensive efforts, understanding the roles of various lipids and lipid biosynthesis enzymes and pathways in (ϩ)RNA virus replication is limited.Tomato bushy stunt virus (TBSV) is among the most advanced model systems regarding the identification of host factors affecting (ϩ)RNA virus replication (32). Among the five proteins encoded by the TBSV genome, only the p33 re...

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“…siRNAs targeting the mevalonate (diphospho) decarboxylase (MVD) enzyme, which catalyzes the formation of mevalonate, were found to inhibit Luc-1b replication (19). Inhibition of the cholesterol biosynthesis pathway and host cell geranylation has been previously reported to inhibit HCV subgenomic replication (3,24,51,62,67). siRNA-mediated knockdown of the class III phosphatidylinositol 4-kinases PI4KA and PI4KB inhibited luciferase expression not only for the genotype 1b subgenomic replicons (Luc-1a and Luc-1b) but also for the viral RNA levels of SG-1b, Luc-1b, and Luc-1a.…”

mentioning

confidence: 99%

Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication

Borawski¹,

Troke²,

Puyang³

et al. 2009

J Virol

178

174

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Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.Hepatitis C virus (HCV) causes liver disease in humans, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (52). The HCV genome is a single-stranded RNA molecule where both the 5Ј and the 3Ј untranslated region (UTR) contain highly conserved RNA structures necessary for polyprotein translation and genome replication (43). The processed polyprotein yields at least three structural proteins and six nonstructural proteins. The structural proteins include the core, which forms the viral nucleocapsid, and the envelope glycoproteins E1 and E2. The viral proteins processed by signal peptidases form viral particles that assemble at the endoplasmic reticulum (ER) and/or Golgi bodies and are released from the host cell by viral budding. The structural protein coding regions are separated from nonstructural proteins by the short membrane peptide p7, thought to function as an ion channel (43, 53). The nonstructural proteins NS2, NS3/4A, NS5A, and NS5B are involved in coordinating the intracellular processes of the virus life cycle, including polyprotein processing and viral RNA replication (34).The Luc-1b cell is a human hepatoma cell line (Huh7) that contains a genotype 1b HCV subgenomic replicon, a luciferase reporter, and a neomycin selection marker, allowing HCV replication to be studied both in vitro and in vivo (8,36). This subgenomic replicon lacks the coding regions for NS2 and the structural proteins but contains the nonstructural proteins in cis, which are required for replicat...

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The influence of cholesterol and lipid metabolism on host cell structure and hepatitis C virus replication

Cited by 75 publications

References 38 publications

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Inhibition of Sterol Biosynthesis Reduces Tombusvirus Replication in Yeast and Plants

Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication

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