Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis

Herwig Koppensteiner,Philippe Benaroch,Kristin Höhne,Anke Heigele,Francois-Xavier Gobert,Marcos Vinicius Gondim,Michael Winkler,Miriam Widder,Frank Kirchhoff,Michael Schindler,Swantje Gundlach

doi:10.1186/1742-4690-11-1

Abstract

BackgroundIncreased 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.ResultsSurface 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.ConclusionInhibition 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.

Highlights

Increased cellular iron levels are associated with high mortality in HIV-1 infection
HIV-1 NA7, NL4-3 and SF2 Nef are highly similar, we considered the possibility that subtle alterations in Nef might be sufficient to allow HfE degradation
Conclusions we establish inhibition of Transferrin Receptor I (TfR) internalization as a novel function that is exerted by most simian immunodeficiency viruses (SIV) Nef proteins in primary T cells and macrophages

Summary

Introduction

Increased cellular iron levels are associated with high mortality in HIV-1 infection. Iron is an important cofactor for viral replication, raising the question whether highly divergent lentiviruses actively modulate iron homeostasis. We evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains. Iron is an essential element in the human body and involved in cellular proliferation and immune response [1]. Since free iron generates harmful reactive oxygen species iron homeostasis is tightly regulated. Loaded on Transferrin (Tf ) iron enters the blood stream and is taken up by target cells via the Transferrin Receptor I (TfR). Internalization of TfR can be antagonized by the hemochromatis protein (HfE). Cells can regulate iron uptake by TfR expression or by the rate

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