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Brinkmann, C.* ; Nehlmeier, I.* ; Walendy-Gnirß, K.* ; Nehls, J. ; González Hernández, M.* ; Hoffmann, M.* ; Qiu, X.* ; Takada, A.* ; Schindler, M. ; Pöhlmann, S.*

Tetherin antagonism by the Ebola virus glycoprotein requires an intact receptor-binding domain and can be blocked by GP1-specific antibodies.

J. Virol. 90, 11075-11086 (2016)
Verlagsversion Postprint DOI PMC
Open Access Green
The glycoprotein of Ebola virus (EBOV-GP), a member of the Filoviridae family, facilitates viral entry into target cells. In addition, EBOV-GP antagonizes the antiviral activity of the host cell protein tetherin, which may otherwise restrict EBOV-release from infected cells. However, it is unclear how EBOV-GP antagonizes tetherin and it is unknown whether the GP of Lloviu virus (LLOV), a filovirus found in dead bats in Northern Spain, also counteracts tetherin. Here, we show that LLOV-GP antagonizes tetherin, indicating that tetherin may not impede LLOV spread in human cells. Moreover, we demonstrate that appropriate processing of N-glycans in tetherin/GP-coexpressing cells is required for tetherin counteraction by EBOV-GP. Furthermore, we show that an intact receptor-binding domain (RBD) in the GP1 subunit of EBOV-GP is a prerequisite to tetherin counteraction. In contrast, blockade of Niemann-Pick disease, type C1 (NPC1), a cellular binding partner of the RBD, did not interfere with tetherin antagonism. Finally, we provide evidence that an antibody directed against GP1, which protects mice from a lethal EBOV challenge, may block GP-dependent tetherin antagonism. Our data in conjunction with previous reports indicate that tetherin antagonism is conserved between the GPs of all known filoviruses and demonstrate that the GP1 subunits of EBOV-GP plays a central role in tetherin antagonism. IMPORTANCE: Filoviruses are re-emerging pathogens that constitute a public health threat. Understanding how Ebola virus (EBOV), a highly pathogenic filovirus responsible for the 2013-2016 Ebola virus disease epidemic in Western Africa, counteracts antiviral effectors of the innate immune system might help to define novel targets for antiviral intervention. Similarly, determining whether Lloviu virus (LLOV), a filovirus detected in bats in Northern Spain, is inhibited by innate antiviral effectors in human cells might help to define whether the virus constitutes a threat to humans. The present study shows that LLOV like EBOV counteracts the antiviral effector protein tetherin via its glycoprotein (GP), suggesting that tetherin does not pose a defense against LLOV spread in humans. Moreover, our work identifies the GP1 subunit of EBOV-GP, in particular an intact receptor-binding domain, as critical for tetherin counteraction and provides evidence that antibodies directed against GP1 can interfere with tetherin counteraction.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Human-immunodeficiency-virus; Niemann-pick C1; Envelope Glycoprotein; Monoclonal-antibodies; Viral Entry; Hiv-1 Vpu; Hemorrhagic-fever; Dc-signr; Protein; Infection
ISSN (print) / ISBN 0022-538X
e-ISSN 1098-5514
Zeitschrift Journal of Virology
Quellenangaben Band: 90, Heft: 24, Seiten: 11075-11086 Artikelnummer: , Supplement: ,
Verlag American Society for Microbiology (ASM)
Verlagsort Washington
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)