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

Retrovirology

Michael Schindler⁶  Philippe Benaroch⁵  Michael Winkler³  Frank Kirchhoff⁴  Anke Heigele⁴  Swantje Gundlach⁶  Miriam Widder¹  Francois-Xavier Gobert⁵  Marcos Vinicius Gondim²  Kristin Höhne⁶  Herwig Koppensteiner⁶ 

[1] Current address: Martin Luther University Halle-Wittenberg, Internal Medicine IV, Halle, Germany;Institute of Virology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany;German Primate Center, Göttingen, Germany;Ulm University Medical Center, Institute of Molecular Virology, Ulm, Germany;Institut Curie, INSERM U932, Paris, France;Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

关键词: Macrophages;    Lentiviral replication;    AIDS;    Iron homeostasis;    Nef;    SIV;    HIV;   

Others  :  804275
DOI  :  10.1186/1742-4690-11-1

 received in 2013-08-12, accepted in 2013-12-20,  发布年份 2014

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2014 Koppensteiner et al.; licensee BioMed Central Ltd.

【 图 表 】

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