Dysregulation der zellulären Eisenaufnahme durch pathogene und apathogene Immundefizienzviren
Final Report Abstract
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. Since it was proposed that HIV-1 Nef might increase cellular iron uptake by inhibition of the hemochromatosis protein HfE, we evaluated the effect on cellular iron uptake upon expression of the accessory protein Nef from different lentiviral strains. Of note, interference with HfE was not conserved among lentiviral Nef proteins and a weak and particular feature of one isolated allele. We furthermore investigated surface Transferrin receptor (TfR) expression levels. These were 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 was dependent on an N-terminal AP2 binding motif which was not required for downmodulation of CD4, CD28, CD3 or MHCI. Importantly, SIV Nef-induced inhibition of TfR endocytosis lead to the reduction of Transferrin uptake and intracellular iron concentration and was accompanied by attenuated lentiviral replication in macrophages. From the cumulated data of this project we conclude that 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. We propose, that in future experiments, the relevance of cellular iron for lentiviral pathogenesis could be studied in appropriate monkey models by exploitation of the selective mutants identified herein.
Publications
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Single Nef proteins from HIV type 1 subtypes C and F fail to upregulate invariant chain cell surface expression but are active for other functions. AIDS Res Hum Retroviruses. 2009 Mar;25(3):285-96
Turk G, Gundlach S, Carobene M, Schindler M, Salomon H, Benaroch P
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(2010) A flow cytometry-based FRET assay to identify and analyse protein-protein interactions in living cells. PLoS ONE 5(2): e9344
Banning C, Votteler J, Hoffmann D, Koppensteiner H, Warmer M, Reimer R, Kirchhoff F, Schubert U, Hauber J, Schindler M
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(2010) HIV-1 assembly in macrophages. Retrovirology, 2010 Apr 7;7:29
Benaroch P, Billard E, Gaudin R, Schindler M, Jouve M
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(2010) Vpu serine 52 dependent counteraction of tetherin is required for HIV-1 replication in macrophages, but not in ex vivo human lymphoid tissue. Retrovirology 2010, 7:1
Schindler M, Rajan D, Banning C, Wimmer P, Koppensteiner H, Iwanski A, Specht A, Sauter D, Dobner T and Kirchhoff F
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(2011) The Ebola virus glycoprotein and HIV-1 Vpu employ different strategies to counteract the antiviral factor tetherin. J Infect Dis. 2011 Nov;204 Suppl 3:S850-60
Kühl A, Banning C, Marzi A, Votteler J, Steffen I, Bertram S, Glowacka I, Konrad A, Stürzl M, Guo JT, Schubert U, Feldmann H, Behrens G, Schindler M, Pöhlmann S
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(2012) Macrophages and their Relevance in Human Immunodeficiency Virus Type I Infection. Retrovirology, 2012, 9:82
Koppensteiner H, Brack-Werner R, Schindler M
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(2013) HIV-1 Vpu affects the anterograde transport and the glycosylation pattern of NTB-A. Virology, 2013 Jun 5;440(2):190-203. Epub 2013 Mar 22.
Bolduan S, Hubel P, Reif T, Hoehne K, Fritz J, Sauter D, Kirchhoff F, Fackler OT, Schindler M, Schubert U
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(2014) Lentiviral Nef suppresses iron uptake in a strain specific manner through inhibition of Transferrin endocytosis. Retrovirology, 2014 Jan 2;11:1
Koppensteiner H, Höhne K, Gondim MV, Gobert FX, Widder M, Gundlach S, Heigele A, Kirchhoff F, Winkler M, Benaroch P, Schindler M
