HIV-1 Nef Down-Regulates the Hemochromatosis Protein HFE, Manipulating Cellular Iron Homeostasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 31; pp. 11017 - 11022
• Main Authors: Drakesmith, Hal, Chen, Nan, Ledermann, Hannah, Screaton, Gavin, Townsend, Alain, Xu, Xiao-Ning, Weatherall, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.08.2005; National Acad Sciences
• Subjects: Biological Sciences; Biological Transport, Active; Cell Line; Cell lines; Cells; Cultured cells; Down regulation; Ferritins; Gene Products, nef - chemistry; Gene Products, nef - genetics; Gene Products, nef - physiology; Genes, nef; HEK293 cells; HeLa Cells; Hemochromatosis - genetics; Hemochromatosis - metabolism; Hemochromatosis Protein; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; HIV; HIV 1; HIV Infections - genetics; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - genetics; HIV-1 - pathogenicity; HIV-1 - physiology; Homeostasis; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; In Vitro Techniques; Iron; Iron - metabolism; Macrophages; Macrophages - metabolism; Macrophages - virology; Medical research; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Monocytes - metabolism; Monocytes - virology; Mutation; nef Gene Products, Human Immunodeficiency Virus; Protein Structure, Tertiary; Proteins; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0504823102

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.