title: HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux.
abstract: HIV infection, through the actions of viral accessory protein Nef, impairs activity of cholesterol transporter ABCA1, inhibiting cholesterol efflux from macrophages and elevating the risk of atherosclerosis. Nef also induces lipid raft formation. In this study, we demonstrate that these activities are tightly linked and affect macrophage function and HIV replication. Nef stimulated lipid raft formation in macrophage cell line RAW 264.7, and lipid rafts were also mobilized in HIV-1-infected human monocyte-derived macrophages. Nef-mediated transfer of cholesterol to lipid rafts competed with the ABCA1-dependent pathway of cholesterol efflux, and pharmacological inhibition of ABCA1 functionality or suppression of ABCA1 expression by RNAi increased Nef-dependent delivery of cholesterol to lipid rafts. Nef reduced cell-surface accessibility of ABCA1 and induced ABCA1 catabolism via the lysosomal pathway. Despite increasing the abundance of lipid rafts, expression of Nef impaired phagocytic functions of macrophages. The infectivity of the virus produced in natural target cells of HIV-1 negatively correlated with the level of ABCA1. These findings demonstrate that Nef-dependent inhibition of ABCA1 is an essential component of the viral replication strategy and underscore the role of ABCA1 as an innate anti-HIV factor.
authors.affiliation: Baker Heart and Diabetes Institute, Melbourne, VIC,  Australia.
authors.forename: Huanhuan L
authors.initials: HL
authors.lastname: Cui
authors.forename: Angela
authors.initials: A
authors.lastname: Grant
authors.forename: Nigora
authors.initials: N
authors.lastname: Mukhamedova
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pushkarsky
authors.forename: Lucas
authors.initials: L
authors.lastname: Jennelle
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubrovsky
authors.forename: Katharina
authors.initials: K
authors.lastname: Gaus
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002122:Calcium Chloride / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002122:Calcium Chloride; D002738:Chloroquine; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D013449:Sulfonamides; D054311:nef Gene Products, Human Immunodeficiency Virus; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C514837:nef protein, Human immunodeficiency virus 1