title: Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection.
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.
authors.affiliation: Unité Hépacivirus et Immunité Innée, CNRS, UMR3569, Paris, France; Dipartimento di Medicina Translazionale, Università del Piemonte Orientale, "Amedeo Avogadro", Novara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Bocchetta
authors.affiliation: Unité Hépacivirus et Immunité Innée, CNRS, UMR3569, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maillard
authors.affiliation: Unité Hépacivirus et Immunité Innée, CNRS, UMR3569, Paris, France; Department of Biochemistry, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: INSERM U1040, Institut de Recherche en Biothérapie, Hôpital Saint-Eloi, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gondeau
authors.affiliation: Groupe de Recherche Dynamique Microbienne et Transmission virale, UMR CNRS 5557, Ecologie Microbienne, Villeurbanne, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Douam
authors.affiliation: Unité Trafic Membranaire et Pathogenèse, Institut Pasteur, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lebreton
authors.affiliation: Unité d'Hépatologie, AP-HP, Groupe Hospitalier Cochin-Hôtel Dieu, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lagaye
authors.affiliation: Unité d'Hépatologie, AP-HP, Groupe Hospitalier Cochin-Hôtel Dieu, Paris, France; Equipe Cycle Cellulaire, Régénération et Hépatopathies, INSERM U1016, CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Laboratoire de Virologie, CHU Sud Amiens, Centre de Biologie Humaine, Amiens, France.
authors.forename: François
authors.initials: F
authors.lastname: Helle
authors.affiliation: Dyslipidemia, Inflammation and Atherosclerosis in Metabolic Diseases, INSERM UMRS939, Paris, France; Endocrinology and Metabolism Unit, Department of Medecine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.
authors.forename: Wanee
authors.initials: W
authors.lastname: Plengpanich
authors.affiliation: Dyslipidemia, Inflammation and Atherosclerosis in Metabolic Diseases, INSERM UMRS939, Paris, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Guérin
authors.affiliation: Pathogénèse des Virus de l'Hépatite B, INSERM U845, Institut Pasteur, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Bourgine
authors.affiliation: Pathogénèse des Virus de l'Hépatite B, INSERM U845, Institut Pasteur, Paris, France.
authors.forename: Marie Louise
authors.initials: ML
authors.lastname: Michel
authors.affiliation: Groupe de Recherche Dynamique Microbienne et Transmission virale, UMR CNRS 5557, Ecologie Microbienne, Villeurbanne, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Lavillette
authors.affiliation: INSERM U966, Université François-Rabelais and CHRU de Tours, Tours, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Roingeard
authors.affiliation: Dyslipidemia, Inflammation and Atherosclerosis in Metabolic Diseases, INSERM UMRS939, Paris, France.
authors.forename: Wilfried
authors.initials: W
authors.lastname: le Goff
authors.affiliation: Unité Hépacivirus et Immunité Innée, CNRS, UMR3569, Paris, France.
authors.forename: Agata
authors.initials: A
authors.lastname: Budkowska
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000821:virology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D021962:Membrane Microdomains / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D014771:Virion / Q000187:drug effects / Q000378:metabolism; D053585:Virus Attachment / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D012367:RNA, Viral; D011991:Receptors, Virus; D002784:Cholesterol