Ist Tetherin zur Behandlung einer Ebola-Infektion geeignet ?

Ein wichtiger Faktor in der antiviralen Immunantwort auf eine Filovirus, wie aber auch eine HIV-1, Infektion ist offenbar Tetherin. Bei Tetherin handelt es sich um einen Wirtsfaktor der durch Alpha-Interferonpräsenz dazu beiträgt, dass Viren und Viruspartikel in infizierten menschlichen Zellen, nicht mehr freigesetzt werden können, wodurch andere Zellen des Organismus vor einer weiteren Infektion durch Viren geschützt werden.

http://de.wikipedia.org/wiki/Tetherin

Im Falle einer Ebola Infektion bewirkt offenbar das GP40 Glykoprotein des Ebola-Virus, das auch bei anderen Filoviren gefunden wurde - zusammen mit GP2 - eine zusätzliche Blockierung der antiviralen Antwort des menschlichen Immunsystems.

Da Tetherin ein Zellprotein ist, wird es wahrscheinlich selbst nicht direkt als Therapeutikum in Frage kommen. Da es aber durch Alpha-Interferon herauf reguliert werden kann ist kommt es als Ziel einer antiinfektiösen Therapie bei einer viral hämorrhagischen Erkrankung wie Ebola oder Marburg in Frage.

Offenbar ist Tetherin einer der Zielorte der antiviralen Wirkung der alpha Interferone.

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Abstract

The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the transmembrane domains of Vpu and tetherin. In contrast, the glycoproteins (GPs) of two filoviruses, Ebola and Marburg virus, antagonize tetherin without reducing surface expression, and the domains in GP required for tetherin counteraction are unknown. Here, we show that filovirus GPs depend on the presence of their authentic transmembrane domains for virus-cell fusion and tetherin antagonism. However, conserved residues within the transmembrane domain were dispensable for membrane fusion and tetherin counteraction. Moreover, the insertion of the transmembrane domain into a heterologous viral GP, Lassa virus GPC, was not sufficient to confer tetherin antagonism to the recipient. Finally, mutation of conserved residues within the fusion peptide of Ebola virus GP inhibited virus-cell fusion but did not ablate tetherin counteraction, indicating that the fusion peptide and the ability of GP to drive host cell entry are not required for tetherin counteraction. These results suggest that the transmembrane domains of filoviral GPs contribute to tetherin antagonism but are not the sole determinants.

Keywords: 

Viruses. Apr 2014; 6(4): 1654–1671.

Published online Apr 9, 2014. doi:  10.3390/v6041654 PMCID: PMC4014715

Analysis of Determinants in Filovirus Glycoproteins Required for Tetherin Antagonism

Kerstin Gnirß,^1,2,† Marie Fiedler,^1,† Annika Krämer-Kühl,^1,2,†‡ Sebastian Bolduan,³ Eva Mittler,^4,# Stephan Becker,⁴Michael Schindler,³ and Stefan Pöhlmann^1,2,*

The host cell protein tetherin can restrict the release of enveloped viruses from infected cells. The HIV-1 protein Vpu counteracts tetherin by removing it from the site of viral budding, the plasma membrane, and this process depends on specific interactions between the transmembrane domains of Vpu and tetherin. In contrast, the glycoproteins (GPs) of two filoviruses, Ebola and Marburg virus, antagonize tetherin without reducing surface expression, and the domains in GP required for tetherin counteraction are unknown. Here, we show that filovirus GPs depend on the presence of their authentic transmembrane domains for virus-cell fusion and tetherin antagonism. However, conserved residues within the transmembrane domain were dispensable for membrane fusion and tetherin counteraction. Moreover, the insertion of the transmembrane domain into a heterologous viral GP, Lassa virus GPC, was not sufficient to confer tetherin antagonism to the recipient. Finally, mutation of conserved residues within the fusion peptide of Ebola virus GP inhibited virus-cell fusion but did not ablate tetherin counteraction, indicating that the fusion peptide and the ability of GP to drive host cell entry are not required for tetherin counteraction. These results suggest that the transmembrane domains of filoviral GPs contribute to tetherin antagonism but are not the sole determinants.

Keywords: tetherin, ebola, lassa, glycoprotein

J Infect Dis. 2011 Nov;204 Suppl 3:S850-60. doi: 10.1093/infdis/jir378.

The Ebola virus glycoprotein and HIV-1 Vpu employ different strategies to counteract the antiviral factor tetherin.

Kühl et al.

Abstract

The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking theEbola virus (EBOV), a hemorrhagic fever virus. The HIV-1 viral protein U (Vpu) and the EBOV-glycoprotein (EBOV-GP) both inhibit tetherin. Here, we compared tetherin counteraction by EBOV-GP and Vpu. We found that EBOV-GP but not Vpu counteracted tetherin from different primate species, indicating that EBOV-GP and Vpu target tetherin differentially. Tetherin interacted with the GP2 subunit of EBOV-GP, which might encode the determinants for tetherin counteraction. Vpu reduced cell surface expression of tetherin while EBOV-GP did not, suggesting that both proteins employ different mechanisms to counteract tetherin. Finally, Marburg virus (MARV)-GP also inhibited tetherin and downregulated tetherin in a cell type-dependent fashion, indicating that tetherin antagonism depends on the cellular source of tetherin. Collectively, our results indicate that EBOV-GP counteracts tetherin by a novel mechanism and that tetherin inhibition is conserved between EBOV-GP and MARV-GP.