HIV-1 Vpu and HIV-2 Env counteract BST-2/tetherin by sequestration in a perinuclear compartment

Hauser, Heiko; Lopez, Lisa A.; Yang, Su Jung; Oldenburg, Jill; Exline, Colin M.; Guatelli, John; Cannon, Paula M.

doi:10.1186/1742-4690-7-51

Cited by 147 publications

(174 citation statements)

References 48 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%

“…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

243

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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“…However, some of these viruses possess their own antagonizing BST2 counterparts instead of Vpu. For instance, HIV-2 counteracts BST2 with its envelope glycoprotein (Env) (8,13,15,30), while SIVsmm/mac impairs the tethering function of simian BST2 with its accessory protein, Nef (15,58,73). In addition, it was reported that Ebola virus glycoprotein (24) and the K5 protein of Kaposi's sarcoma-associated herpesvirus (34,46) can counteract BST2.…”

Section: Wt]) Hiv-1-infected/transfected Cells In Certain Cd4mentioning

confidence: 99%

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

Sato

Misawa

Fukuhara

et al. 2012

J Virol

122

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While human cells express potent antiviral proteins as part of the host defense repertoire, viruses have evolved their own arsenal of proteins to antagonize them. BST2 was identified as an inhibitory cellular protein of HIV-1 replication, which tethers virions to the cell surface to prevent their release. On the other hand, the HIV-1 accessory protein, Vpu, has the ability to downregulate and counteract BST2. Vpu also possesses the ability to downmodulate cellular CD4 and SLAMF6 molecules expressed on infected cells. However, the role of Vpu in HIV-1 infection in vivo remains unclear. Here, using a human hematopoietic stem celltransplanted humanized mouse model, we demonstrate that Vpu contributes to the efficient spread of HIV-1 in vivo during the acute phase of infection. Although Vpu did not affect viral cytopathicity, target cell preference, and the level of viral protein expression, the amount of cell-free virions in vpu-deficient HIV-1-infected mice was profoundly lower than that in wild-type HIV-1-infected mice. We provide a novel insight suggesting that Vpu concomitantly downregulates BST2 and CD4, but not SLAMF6, from the surface of infected cells. Furthermore, we show evidence suggesting that BST2 and CD4 impair the production of cellfree infectious virions but do not associate with the efficiency of cell-to-cell HIV-1 transmission. Taken together, our findings suggest that Vpu downmodulates BST2 and CD4 in infected cells and augments the initial burst of HIV-1 replication in vivo. This is the first report demonstrating the role of Vpu in HIV-1 infection in an in vivo model.

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HIV-1 Vpu and HIV-2 Env counteract BST-2/tetherin by sequestration in a perinuclear compartment

Cited by 147 publications

References 48 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

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

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