Charakterisierung des antiviralen Immunfaktors CD317/tetherin
Zusammenfassung der Projektergebnisse
During the two funding periods the Fackler and Keppler laboratories thus far published a total of 11 papers in international journals, including Nature Medicine, PNAS and Cell Host Microbe with a focus on the restriction factor CD317/THN and its viral antagonist, Vpu. Basic insight was reached regarding Vpu’s mode of counteraction, essential motifs and trafficking machinery and its ability to affect in a very general way, similar to Nef, the surface proteome to optimize the infected cell’s environment for replication and virus egress. A screening approach identified a set of novel Vpu interactors the validation of which for CD317/THN antagonism and other Vpu functions is ongoing. As part of our extended restriction factor characterization, we established the micro-array-based tissue expression profiling for both CD317/THN and SAMHD1. Recent work also identified an unexpected role of SAMHD1 in chemoresistance of acute myeloid leukemia to specific nucleoside analogs. Collectively, this joint project advanced the fundamental insight into physiological HIV restriction factor expression patterns and modes of interference by the lentiviral Vpu protein.
Projektbezogene Publikationen (Auswahl)
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HIV-1 Vpu blocks recycling and biosynthetic transport of the intrinsic immunity factor CD317/Tetherin to overcome the virion release restriction. mBio 2:e00036-11 (2011)
Schmidt S, Fritz J, Bitzegeio J, Fackler OT, Keppler OT
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In vivo-expression profile of the antiviral restriction factor and tumor-targeting antigen CD317/BST-2/ HM1.24/tetherin in humans. Proc. Natl. Acad. Sci. USA 108:13688-13693 (2011)
Erikson E, Adam T, Schmidt S, Lehmann-Koch J, Over B, Goffinet C, Harter C, Bekeredjian-Ding I, Sertel S, Lasitschka F, Keppler OT
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β-TrCP is dispensable for Vpu’s ability to overcome the CD317/Tetherin-imposed restriction to HIV-1 release. Retrovirology 8:9 (2011)
Tervo H-M, Homann S, Ambiel I, Fritz J, Fackler OT, Keppler OT
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Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. PLoS Path. 8:e1003093 (2012)
Sauter D, Unterweger D, Vogl M, Usmani SM, Heigele A, Kluge SF, Hermkes E, Moll M, Barker E, Peeters M, Learn GH, Bibollet-Ruche F, Fritz JV, Fackler OT, Hahn BH, Kirchhoff F
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Membrane microdomain association of HIV-1 Vpu is dispensable for counteracting the particle release restriction imposed by CD317/BST-2/Tetherin. Virology 424:33-44 (2012)
Fritz JV, Tibroni N, Keppler OT, Fackler OT
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Reacquisition of Nef-mediated tetherin antagonism in a single in vivo passage of HIV-1 through its original chimpanzee host. Cell Host Microbe 12:373-80 (2012)
Götz N, Sauter D, Usmani SM, Fritz JV, Goffinet C, Heigele A, Geyer M, Bibollet-Ruche F, Learn GH, Fackler OT, Hahn BH, Kirchhoff F
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HIV-1 Nef and Vpu are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors Including Tetraspanins. J. Virol., 88:14241-57 (2014)
Haller C, Müller B, Fritz JV, Lamas-Murua M, Stolp B, Pujol F, Keppler OT, Fackler OT
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Nef proteins of epidemic HIV- 1 group O strains antagonize human tetherin. Cell Host Microbe, 5: 639–650 (2014)
Kluge SF, Mack K, Iyer SS, Pujol FM, Heigele A, Learn GH, Usmani SH, Sauter D, Joas S, Hotter D, Bibollet-Ruche F, Plenderleith LJ, Peeters M, Geyer M, Sharp PM, Fackler OT, Hahn BH, Kirchhoff F
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SAMHD1's protein expression profile in humans. J. Leukoc. Biol., 98:5-14 (2015)
Schmidt S, Schenkova K, Adam T, Erikson E, Lehmann-Koch J, Sertel S, Verhasselt B, Fackler OT, Lasitschka F, Keppler OT
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HIV-1 Vpu Antagonizes CD317/tetherin by Adaptor protein-1-Mediated Exclusion from Virus Assembly Sites. J. Virol., 90:6709-6723 (2016)
Pujol FM, Laketa V, Schmidt F, Mukenhirn M, Müller B, Boulant S, Grimm D, Keppler OT, Fackler OT
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SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat. Med., 23:250-255 (2017)
Schneider C, Oellerich T, Baldauf H-M, Schwarz S-M, Thomas D, Flick R, Bohnenberger H, Kaderali L, Stegmann L, Cremer A, Martin M, Lohmeyer J, Michaelis M, Hornung V, Schliemann C, Berdel WE, Hartmann W, Wardelmann E, Comoglio F, Hansmann ML, Yakunin AF, Geisslinger G, Ströbel P, Ferreirós N, Serve H, Keppler OT, Cinatl J Jr.
