Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Tortorec, Anna Le; Neil, Stuart J. D.

doi:10.1128/jvi.01515-09

Cited by 260 publications

(375 citation statements)

References 51 publications

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“…This Env‐mediated neutralization of BST‐2 effect is similarly to the antagonistic actions of Vpu 93, 94 and as reported earlier for Vpu in promoting viral particle release 95, 96, 97, 98, 99. Env interacts with BST‐2 but the domains involved in the interaction are yet to be identified.…”

Section: Viral Glycoproteins and Bst‐2 Neutralizationsupporting

confidence: 77%

The role of BST‐2/Tetherin in host protection and disease manifestation

Mahauad‐Fernandez

Okeoma

2015

Immunity, Inflammation and Disease

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Host cells respond to viral infections by activating immune response genes that are not only involved in inflammation, but may also predispose cells to cancerous transformation. One such gene is BST‐2, a type II transmembrane protein with a unique topology that endows it tethering and signaling potential. Through this ability to tether and signal, BST‐2 regulates host response to viral infection either by inhibiting release of nascent viral particles or in some models inhibiting viral dissemination. However, despite its antiviral functions, BST‐2 is involved in disease manifestation, a function linked to the ability of BST‐2 to promote cell‐to‐cell interaction. Therefore, modulating BST‐2 expression and/or activity has the potential to influence course of disease.

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Section: Viral Glycoproteins and Bst‐2 Neutralizationsupporting

confidence: 77%

The role of BST‐2/Tetherin in host protection and disease manifestation

Mahauad‐Fernandez

Okeoma

2015

Immunity, Inflammation and Disease

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“…Indeed, prior to the identification of tetherin, the envelope glycoproteins of certain HIV-2 isolates were shown to have "Vpu-like" activity that could rescue the release of Vpu-deficient HIV-1 from restrictive cells (62). Tetherin antagonism by Env depends on physical interaction between Env and tetherin and on a conserved tyrosine-based endocytosis motif (YXX) in the cytoplasmic tail of the Env transmembrane protein gp41 (59,60,63). The residues that contribute to Env-tetherin interactions are not well defined but appear to be located in the extracellular domains of both proteins based on analyses of recombinant forms of Env and tetherin (60,64) and on the identification of defined amino acid changes in the ectodomains of gp41 and tetherin that disrupt anti-tetherin activity (64 -66).…”

Section: Restriction By Particle Tethering: Bst-2/tetherin Integral Mmentioning

confidence: 99%

“…Tetherin antagonism by Env depends on physical interaction between Env and tetherin and on a conserved tyrosine-based endocytosis motif (YXX) in the cytoplasmic tail of the Env transmembrane protein gp41 (59,60,63). The residues that contribute to Env-tetherin interactions are not well defined but appear to be located in the extracellular domains of both proteins based on analyses of recombinant forms of Env and tetherin (60,64) and on the identification of defined amino acid changes in the ectodomains of gp41 and tetherin that disrupt anti-tetherin activity (64 -66). Interaction with Env does not result in the degradation of tetherin but instead leads to internalization and sequestration of tetherin away from sites of virus release at the plasma membrane by a clathrin-dependent pathway (57,60,63).…”

Section: Restriction By Particle Tethering: Bst-2/tetherin Integral Mmentioning

confidence: 99%

The Restriction Factors of Human Immunodeficiency Virus

Harris

Hultquist

Evans

2012

Journal of Biological Chemistry

245

255

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Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. Restriction Factor HallmarksRestriction factors have at least four defining characteristics (see Fig. 1A). First and foremost, a restriction factor must directly and dominantly cause a significant decrease in HIV infectivity. This is often determined by cotransfecting cell lines such as HEK293 and HeLa with a molecular clone of the virus, with or without a plasmid expressing the restriction factor, and measuring the amount and infectivity of virus recovered in the cell culture medium after 1-2 days of incubation. Such assays are ideally done over a range of restriction factor expression, with the highest levels often imposing log-scale drops in viral infectivity (see Fig. 1B). This "single-cycle" assay for viral replication is useful for testing the impact of viral mutations and/or restriction factor variations.Second, if a restriction factor is a true threat to viral replication, then the predecessors of HIV invariably evolved an equally potent counter-restriction mechanism that still exists in the present day virus. For instance, titrating a counter-restriction factor into the aforementioned single-cycle infectivity experiment can result in a full recovery of viral infectivity despite the presence of an active restriction factor (Fig. 1B). Viruses lacking these various countermeasures are able to replicate in some, but not all, cell types depending on the expression level of the relevant restriction factor. Cell lines that support replication are termed "permissive," and those that do not are termed "nonpermissive." This life/death dichotomy has been elegantly exploited to identify several restriction factors and their corresponding viral antagonists.Third, because the interactions between restriction and counter-restriction factors occur through direct protein-protein interactions, the restriction factor often shows signatures of rapid evolution. In general, mutations are maintained in a population only if they confer a selective advantage. If a host species experiences iterative rounds of pathogenic pressure, altered variants of host restriction factors that are no longer susceptible to the pathogen's counteraction mechanism are selected. Over evolutionary time, this results in an overabundance of amino acid substitution mutations in these genes relative to non-amino acid...

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“…Many simian immunodeficiency variants do not encode a Vpu protein, suggesting the existence of an alternative means of overcoming tetherin restriction. Indeed, HIV-2 envelope protein has been reported to promote viral budding (12)(13)(14)(15), and two recent reports demonstrate that this is the result of tetherin antagonism (3,16). Remarkably, Ebola virus glycoprotein has also been reported to have antitetherin activity, suggesting that envelope glycoproteins may commonly have anti-tetherin function (17).…”

mentioning

confidence: 99%

Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration

Mlčochová²,

Pelchen–Matthews³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

150

185

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Tetherin is an IFN-inducible restriction factor that inhibits HIV-1 particle release in the absence of the HIV-1 countermeasure, viral protein U (Vpu). Although ubiquitous in HIV-1 and simian immunodeficiency viruses from chimpanzees, greater spot nosed monkeys, mustached monkeys, and Mona monkeys, other primate lentiviruses do not encode a Vpu protein. Here we demonstrate that SIV from Tantalus monkeys (SIVtan) encodes an envelope glycoprotein (SIVtan Env) able to counteract tetherin from Tantalus monkeys, rhesus monkeys, sooty mangabeys, and humans, but not from pigs. We show that sensitivity to Vpu but not SIVtan Env can be transferred with the human tetherin transmembrane region. We also identify a mutation in the tetherin extracellular domain, which almost completely abolishes sensitivity of human tetherin to SIVtan Env without compromising antiviral activity or sensitivity to Vpu. SIVtan Env expression results in a reduction of surface tetherin, as well as reduction in tetherin co-localization with mature surface-associated virus. Immuno-electron microscopy reveals co-localization of SIVtan Env with tetherin in intracellular tubulo-vesicular structures, suggesting that tetherin is sequestered away from budding virions at the cell surface. Along with HIV-1 Vpu and SIV Nef, envelope glycoprotein is the third and most broadly active lentiviral-encoded tetherin countermeasure to be described. Our observations emphasize the importance of tetherin in protecting mammals against viral infection and suggest that HIV-1 Vpu inhibitors may select active envelope mutants.HIV ͉ restriction ͉ innate immunity

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Antagonism to and Intracellular Sequestration of Human Tetherin by the Human Immunodeficiency Virus Type 2 Envelope Glycoprotein

Cited by 260 publications

References 51 publications

The role of BST‐2/Tetherin in host protection and disease manifestation

The role of BST‐2/Tetherin in host protection and disease manifestation

The Restriction Factors of Human Immunodeficiency Virus

Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration

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