Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses

Sauter, Daniel; Vogl, Michael; Kirchhoff, Frank

doi:10.1002/humu.21571

Cited by 29 publications

(20 citation statements)

References 15 publications

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“…Importantly this was accompanied by KM-to-RV changes adjacent to Y8 as well as residues upstream of Y6 that facilitated interaction with Syk to create a noncanonical hemITAM. Finally, the 5 amino acid indel that occurred after hominids and chimpanzees diverged (Sauter et al., 2011) enhanced this signaling capacity (Galão et al., 2012). Since some of these differences encompass residues that have been identified as modulating sensitivity to lentiviral Nefs (the indel) and Vpus (the TM insertion) (reviewed in Neil, 2013), we speculate that at least some of these changes may have resulted from pathogen counteraction of tetherin’s antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

Retroviral Retention Activates a Syk-Dependent HemITAM in Human Tetherin

Galão

Pickering

Curnock

et al. 2014

Cell Host & Microbe

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SummaryTetherin (BST2/CD317) restricts the release of enveloped viral particles from infected cells. Coupled to this virion retention, hominid tetherins induce proinflammatory gene expression via activating NF-κB. We investigated the events initiating this tetherin-induced signaling and show that physical retention of retroviral particles induces the phosphorylation of conserved tyrosine residues in the cytoplasmic tails of tetherin dimers. This phosphorylation induces the recruitment of spleen tyrosine kinase (Syk), which is required for downstream NF-κB activation, indicating that the tetherin cytoplasmic tail resembles the hemi-immunoreceptor tyrosine-based activation motifs (hemITAMs) found in C-type lectin pattern recognition receptors. Retroviral-induced tetherin signaling is coupled to the cortical actin cytoskeleton via the Rac-GAP-containing protein RICH2 (ARHGAP44), and a naturally occurring tetherin polymorphism with reduced RICH2 binding exhibits decreased phosphorylation and NF-κB activation. Thus, upon virion retention, this linkage to the actin cytoskeleton likely triggers tetherin phosphorylation and subsequent signal transduction to induce an antiviral state.

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Section: Discussionmentioning

confidence: 99%

Retroviral Retention Activates a Syk-Dependent HemITAM in Human Tetherin

Galão

Pickering

Curnock

et al. 2014

Cell Host & Microbe

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“…Nef targets a 5-amino-acid motif in the cytoplasmic domain of simian BST-2 (43,44,49). Of note, this motif is not found in human BST-2 and appears to have been lost more than 800,000 years ago (69). The transmission of SIV to humans is a fairly recent event, and it is interesting that during adaptation to humans, the virus somehow shifted the burden of antagonizing BST-2 from Nef to Vpu (reviewed in reference 70).…”

Section: Discussionmentioning

confidence: 99%

Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions

Yoshida

Koyanagi

Strebel

2013

J Virol

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bHuman immunodeficiency virus type 1 (HIV-1) Vpu enhances the release of viral particles from infected cells by interfering with the function of BST-2/tetherin, a cellular protein inhibiting virus release. The Vpu protein encoded by NL4-3, a widely used HIV-1 laboratory strain, antagonizes human BST-2 but not monkey or murine BST-2, leading to the conclusion that BST-2 antagonism by Vpu is species specific. In contrast, we recently identified several primary Vpu isolates, such as Vpu of HIV-1 DH12 , capable of antagonizing both human and rhesus BST-2. Here we report that while Vpu interacts with human BST-2 primarily through their respective transmembrane domains, antagonism of rhesus BST-2 by Vpu involved an interaction of their cytoplasmic domains. Importantly, a Vpu mutant carrying two mutations in its transmembrane domain (A 14 L and W 22 A), rendering it incompetent for interaction with human BST-2, was able to interact with human BST-2 carrying the rhesus BST-2 cytoplasmic domain and partially neutralized the ability of this BST-2 variant to inhibit viral release. Bimolecular fluorescence complementation analysis to detect Vpu-BST-2 interactions suggested that the physical interaction of Vpu with rhesus or chimpanzee BST-2 involves a 5-residue motif in the cytoplasmic domain of BST-2 previously identified as important for the antagonism of monkey and great ape BST-2 by simian immunodeficiency virus (SIV) Nef. Thus, our study identifies a novel mechanism of antagonism of monkey and great ape BST-2 by Vpu that targets the same motif in BST-2 used by SIV Nef and might explain the expanded host range observed for Vpu isolates in our previous study.

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“…As a broad acting antiviral effector, a deletion in Tetherin could have been selected in response to any number of enveloped viruses. However, this deletion spans residues necessary for antagonism by the lentiviral Nef protein used by many SIV strains, suggesting that it may have been selected by a pathogenic, Nef-encoding lentivirus approximately 800 000 years ago (figure 4) [44,45,76]. Therefore, changes in innate immune genes of humans may have been triggered by previous lentivirus infections in our recent ancestors.…”

Section: Ebb and Flow Of The Lentivirus Reservoir: Virus Extinction Amentioning

confidence: 99%

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

Compton

Malik

Emerman

2013

Phil. Trans. R. Soc. B

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Simian immunodeficiency viruses (SIVs) have infected primate species long before human immunodeficiency virus has infected humans. Dozens of species-specific lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate lentiviruses, but also the pathogenic potential of their modern counterparts.

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Ancient origin of a deletion in human BST2/Tetherin that confers protection against viral zoonoses

Cited by 29 publications

References 15 publications

Retroviral Retention Activates a Syk-Dependent HemITAM in Human Tetherin

Retroviral Retention Activates a Syk-Dependent HemITAM in Human Tetherin

Functional Antagonism of Rhesus Macaque and Chimpanzee BST-2 by HIV-1 Vpu Is Mediated by Cytoplasmic Domain Interactions

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

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