HIV-1 Nef down-regulates the hemochromatosis protein HFE, manipulating cellular iron homeostasis.
The multifunctional Nef protein of HIV-1 is important for the progression to AIDS. One action of Nef is to down-regulate surface MHC I molecules, helping infected cells to evade immunity. We found that Nef also down-regulates the macrophage-expressed MHC 1b protein HFE, which regulates iron homeostasis and is mutated in the iron-overloading disorder hemochromatosis. In model cell lines, Nef reroutes HFE to a perinuclear structure that overlaps the trans-Golgi network, causing a 90% reduction of surface HFE. This activity requires a Src-kinase-binding proline-rich domain of Nef and a conserved tyrosine-based motif in the cytoplasmic tail of HFE. HIV-1 infection of ex vivo macrophages similarly down-regulates naturally expressed surface HFE in a Nef-dependent manner. The effect of Nef expression on cellular iron was explored; iron and ferritin accumulation were increased in HIV-1-infected ex vivo macrophages expressing wild-type HFE, but this effect was lost with Nef-deleted HIV-1 or when infecting macrophages from hemochromatosis patients expressing mutated HFE. The iron accumulation in HIV-1-infected HFE-expressing macrophages was paralleled by an increase in cellular HIV-1-gag expression. We conclude that, through Nef and HFE, HIV-1 directly regulates cellular iron metabolism, possibly benefiting viral growth.
Drakesmith
Hal
H
Molecular Immunology Group and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom. hdrakes@hammer.imm.ox.ac.uk
Chen
Nan
N
Ledermann
Hannah
H
Screaton
Gavin
G
Townsend
Alain
A
Xu
Xiao-Ning
XN
D001693:Biological Transport, Active; D002460:Cell Line; D015536:Down-Regulation; D015693:Gene Products, nef / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015754:Genes, nef; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006367:HeLa Cells; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D009154:Mutation; D017434:Protein Structure, Tertiary; D054311:nef Gene Products, Human Immunodeficiency Virus
D015693:Gene Products, nef; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D007501:Iron