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

ABSTRACT: The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking the Ebola 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.

SUBMITTER: Kuhl A

PROVIDER: S-EPMC3189996 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Kühl Annika A Banning Carina C Marzi Andrea A Votteler Jörg J Steffen Imke I Bertram Stephanie S Glowacka Ilona I Konrad Andreas A Stürzl Michael M Guo Ju-Tao JT Schubert Ulrich U Feldmann Heinz H Behrens Georg G Schindler Michael M Pöhlmann Stefan S

The Journal of infectious diseases 20111101

The antiviral protein tetherin/BST2/CD317/HM1.24 restricts cellular egress of human immunodeficiency virus (HIV) and of particles mimicking the Ebola 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. Tethe ...[more]

PMID: 21987761

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Project description:Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4+ T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.IMPORTANCE Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms.

Project description:Tetherin, an interferon-induced host protein encoded by the bone marrow stromal antigen 2 (BST2/CD317/HM1.24) gene, is involved in obstructing the release of many retroviruses and other enveloped viruses by cross-linking the budding virus particles to the cell surface. This activity is antagonized in the case of human immunodeficiency virus (HIV)-1 wherein its accessory protein Viral Protein U (Vpu) interacts with tetherin, causing its downregulation from the cell surface. Vpu and tetherin connect through their transmembrane (TM) domains, culminating into events leading to tetherin degradation by recruitment of β-TrCP2. However, mutations in the TM domains of both proteins are reported to act as a resistance mechanism to Vpu countermeasure impacting tetherin's sensitivity towards Vpu but retaining its antiviral activity. Our study illustrates the binding aspects of blood-derived, brain-derived, and consensus HIV-1 Vpu with tetherin through protein-protein docking. The analysis of the bound complexes confirms the blood-derived Vpu-tetherin complex to have the best binding affinity as compared to other two. The mutations in tetherin and Vpu are devised computationally and are subjected to protein-protein interactions. The complexes are tested for their binding affinities, residue connections, hydrophobic forces, and, finally, the effect of mutation on their interactions. The single point mutations in tetherin at positions L23Y, L24T, and P40T, and triple mutations at {L22S, F44Y, L37I} and {L23T, L37T, T45I}, while single point mutations in Vpu at positions A19H and W23Y and triplet of mutations at {V10K, A11L, A19T}, {V14T, I18T, I26S}, and {A11T, V14L, A15T} have revealed no polar contacts with minimal hydrophobic interactions between Vpu and tetherin, resulting in reduced binding affinity. Additionally, we have explored the aggregation potential of tetherin and its association with the brain-derived Vpu protein. This work is a possible step toward an understanding of Vpu-tetherin interactions.

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

Publications

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

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