title: Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis.
abstract: BACKGROUND
  Increased cellular iron levels are associated with high mortality in HIV-1 infection. Moreover iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. Here, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains.
  
  
  RESULTS
  Surface Transferrin receptor (TfR) levels are unaffected by Nef proteins of HIV-1 and its simian precursors but elevated in cells expressing Nefs from most other primate lentiviruses due to reduced TfR internalization. The SIV Nef-mediated reduction of TfR endocytosis is dependent on an N-terminal AP2 binding motif that is not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis leads to the reduction of Transferrin uptake and intracellular iron concentration and is accompanied by attenuated lentiviral replication in macrophages.
  
  
  CONCLUSIONS
  Inhibition of Transferrin and thereby iron uptake by SIV Nef might limit viral replication in myeloid cells. Furthermore, this new SIV Nef function could represent a virus-host adaptation that evolved in natural SIV-infected monkeys.
authors.forename: Herwig
authors.initials: H
authors.lastname: Koppensteiner
authors.forename: Kristin
authors.initials: K
authors.lastname: Höhne
authors.forename: Marcos Vinicius
authors.initials: MV
authors.lastname: Gondim
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Gobert
authors.forename: Miriam
authors.initials: M
authors.lastname: Widder
authors.forename: Swantje
authors.initials: S
authors.lastname: Gundlach
authors.forename: Anke
authors.initials: A
authors.lastname: Heigele
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
authors.forename: Michael
authors.initials: M
authors.lastname: Winkler
authors.forename: Philippe
authors.initials: P
authors.lastname: Benaroch
authors.affiliation: Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany. michael.schindler@helmholtz-muenchen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schindler
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000187:drug effects*; D015693:Gene Products, nef / Q000378:metabolism*; D000882:Haplorhini; D007501:Iron / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000037:antagonists & inhibitors*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014168:Transferrin / Q000378:metabolism*
chemical_list: D015693:Gene Products, nef; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron