title: Circulating Nef induces dyslipidemia in simian immunodeficiency virus-infected macaques by suppressing cholesterol efflux.
abstract: Human immunodeficiency virus (HIV) infection and subsequent antiretroviral therapy have been associated with an increased incidence of dyslipidemia and cardiovascular disease and has been shown to suppress cholesterol efflux from virus-infected macrophages by inducing Nef-dependent down-regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1). Here, the simian immunodeficiency virus (SIV)-infected macaque model was used to examine the consequences and mechanisms involved. SIV infection drove a significant remodeling of high-density lipoprotein profiles, suggesting that systemic inhibition of the ABCA1-dependent reverse cholesterol transport pathway occurred. The ABCA1 cholesterol transporter was significantly down-regulated in the livers of the SIV-infected macaques, and the viral protein Nef could be detected in the livers as well as in the plasma of infected animals. Extracellular myristoylated HIV Nef inhibited cholesterol efflux from macrophages and hepatocytes. Moreover, serum samples from SIV-infected macaques also suppressed cholesterol efflux in a Nef-dependent fashion. These results indicate that SIV infection is a significant contributor to primary dyslipidemia, likely through the ability of Nef to suppress ABCA1-dependent reverse cholesterol transport.
authors.affiliation: Lipid Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts, USA.
authors.forename: Bela F
authors.initials: BF
authors.lastname: Asztalos
authors.forename: Zahedi
authors.initials: Z
authors.lastname: Mujawar
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Morrow
authors.forename: Angela
authors.initials: A
authors.lastname: Grant
authors.forename: Tatiana
authors.initials: T
authors.lastname: Pushkarsky
authors.forename: Christine
authors.initials: C
authors.lastname: Wanke
authors.forename: Richard
authors.initials: R
authors.lastname: Shannon
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: Dmitri
authors.initials: D
authors.lastname: Sviridov
authors.forename: Michael L
authors.initials: ML
authors.lastname: Fitzgerald
authors.forename: Michael
authors.initials: M
authors.lastname: Bukrinsky
authors.forename: Keith G
authors.initials: KG
authors.lastname: Mansfield
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D050171:Dyslipidemias / Q000097:blood*; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000503:physiopathology; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000032:analysis / Q000097:blood*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D054311:nef Gene Products, Human Immunodeficiency Virus; D002784:Cholesterol