title: Understanding the molecular mechanism of host-based statin resistance in hepatitis C virus replicon containing cells.
abstract: A number of statins, the cholesterol-lowering drugs, inhibit the in vitro replication of hepatitis C virus (HCV). In HCV-infected patients, addition of statins to the earlier standard of care therapy (pegIFN-α and ribavirin) resulted in increased sustained virological response rates. The mechanism by which statins inhibit HCV replication has not yet been elucidated. In an attempt to gain insight in the underlying mechanism, hepatoma cells carrying an HCV replicon were passaged in the presence of increasing concentrations of fluvastatin. Fluvastatin-resistant replicon containing cells could be generated and proved ∼8-fold less susceptible to fluvastatin than wild-type cultures. The growth efficiency of the resistant replicon containing cells was comparable to that of wild-type replicon cells. The fluvastatin-resistant phenotype was not conferred by mutations in the viral genome but is caused by cellular changes. The resistant cell line had a markedly increased HMG-CoA reductase expression upon statin treatment. Furthermore, the expression of the efflux transporter P-gp was increased in fluvastatin-resistant replicon cells (determined by qRT-PCR and flow cytometry). This increased expression resulted also in an increased functional transport activity as measured by the P-gp mediated efflux of calcein AM. In conclusion, we demonstrate that statin resistance in HCV replicon containing hepatoma cells is conferred by changes in the cellular environment.
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Leen.Delang@rega.kuleuven.be.
authors.forename: Leen
authors.initials: L
authors.lastname: Delang
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Els.Scheers@rega.kuleuven.be.
authors.forename: Els
authors.initials: E
authors.lastname: Scheers
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Mareike.Grabner@rega.kuleuven.be.
authors.forename: Mareike
authors.initials: M
authors.lastname: Grabner
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Ben.Verpaalen@rega.kuleuven.be.
authors.forename: Ben
authors.initials: B
authors.lastname: Verpaalen
authors.affiliation: Stem Cell Biology and Embryology, University of Leuven, O&N IV Herestraat 49 - bus 804, 3000 Leuven, Belgium. Electronic address: Nicky.Helsen@med.kuleuven.be.
authors.forename: Nicky
authors.initials: N
authors.lastname: Helsen
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Els.Vanstreels@rega.kuleuven.be.
authors.forename: Els
authors.initials: E
authors.lastname: Vanstreels
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Dirk.Daelemans@rega.kuleuven.be.
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.affiliation: Stem Cell Biology and Embryology, University of Leuven, O&N IV Herestraat 49 - bus 804, 3000 Leuven, Belgium. Electronic address: Catherine.Verfaillie@med.kuleuven.be.
authors.forename: Catherine
authors.initials: C
authors.lastname: Verfaillie
authors.affiliation: Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: Johan.Neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002219:Carbamates; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral; D004789:Enzyme Activation; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D011759:Pyrrolidines; D012093:Replicon; D015398:Signal Transduction; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000924:Anticholesteremic Agents; D000998:Antiviral Agents; D002219:Carbamates; D005229:Fatty Acids, Monounsaturated; D007093:Imidazoles; D007211:Indoles; D009842:Oligopeptides; D011759:Pyrrolidines; D014764:Viral Proteins; D000077340:Fluvastatin; C486464:telaprevir; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D014633:Valine; C549273:daclatasvir
keywords: Efflux; HMG-CoA reductase; Hepatitis C virus; Resistance; Statins