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      A Single Nucleotide Polymorphism in Tetherin Promotes Retrovirus Restriction In Vivo

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          Abstract

          Tetherin is a membrane protein of unusual topology expressed from rodents to humans that accumulates enveloped virus particles on the surface of infected cells. However, whether this ‘tethering’ activity promotes or restricts retroviral spread during acute retrovirus infection in vivo is controversial. We report here the identification of a single nucleotide polymorphism in the Tetherin gene of NZW/LacJ (NZW) mice that mutated the canonical ATG start site to GTG. Translation of NZW Tetherin from downstream ATGs deleted a conserved dual-tyrosine endosomal sorting motif, resulting in higher cell surface expression and more potent inhibition of Friend retrovirus release compared to C57BL/6 (B6) Tetherin in vitro. Analysis of (B6×NZW)F 1 hybrid mice revealed that increased Tetherin cell surface expression in NZW mice is a recessive trait in vivo. Using a classical genetic backcrossing approach, NZW Tetherin expression strongly correlated with decreased Friend retrovirus replication and pathogenesis. However, the protective effect of NZW Tetherin was not observed in the context of B6 Apobec3/ Rfv3 resistance. These findings identify the first functional Tetherin polymorphism within a mammalian host, demonstrate that Tetherin cell surface expression is a key parameter for retroviral restriction, and suggest the existence of a restriction factor hierarchy to counteract pathogenic retrovirus infections in vivo.

          Author Summary

          Significant portions of the human and mouse genomes are comprised of retroviral sequences, revealing the long history of conflict between mammalian hosts and retroviruses that led to the evolution of host restriction factors. Nucleotide mutations in restriction factor genes provide a glimpse of this ongoing evolutionary process, but studies that directly probe the impact of restriction factor mutations during retrovirus infection are limited. In this study, we identified a single nucleotide mutation in the Tetherin host restriction gene that resulted in retention of Tetherin on the cell surface. In cell culture, Tetherin accumulates virions on the infected cell surface and prevents virion release, but some studies suggested that Tetherin might facilitate cell-to-cell virus spread. Our studies reveal that the Tetherin polymorphism inhibits retrovirus replication and disease. Thus, increased Tetherin cell surface expression enhanced the antiretroviral function of Tetherin. These results could have important implications in harnessing the biology of Tetherin for controlling pathogenic retroviruses such as HIV-1.

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          Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

          Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.
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            The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein.

            The HIV-1 accessory protein Vpu counteracts a host factor that restricts virion release from infected cells. Here we show that the interferon-induced cellular protein BST-2/HM1.24/CD317 is such a factor. BST-2 is downregulated from the cell surface by Vpu, and BST-2 is specifically expressed in cells that support the vpu phenotype. Exogenous expression of BST-2 inhibits HIV-1 virion release, while suppression of BST-2 relieves the requirement for Vpu. Downregulation of BST-2 requires both the transmembrane/ion channel domain and conserved serines in the cytoplasmic domain of Vpu. Endogenous BST-2 colocalizes with the HIV-1 structural protein Gag in endosomes and at the plasma membrane, suggesting that BST-2 traps virions within and on infected cells. The unusual structure of BST-2, which includes a transmembrane domain and a lumenal GPI anchor, may allow it to retain nascent enveloped virions on cellular membranes, providing a mechanism of viral restriction counteracted by a specific viral accessory protein.
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              Tetherin inhibits HIV-1 release by directly tethering virions to cells.

              Tetherin is an interferon-induced protein whose expression blocks the release of HIV-1 and other enveloped viral particles. The underlying mechanism by which tetherin functions and whether it directly or indirectly causes virion retention are unknown. Here, we elucidate the mechanism by which tetherin exerts its antiviral activity. We demonstrate, through mutational analyses and domain replacement experiments, that tetherin configuration rather than primary sequence is critical for antiviral activity. These findings allowed the design of a completely artificial protein, lacking sequence homology with native tetherin, that nevertheless mimicked its antiviral activity. We further show that tetherin is incorporated into HIV-1 particles as a parallel homodimer using either of its two membrane anchors. These results indicate that tetherin functions autonomously and directly and that infiltration of virion envelopes by one or both of tetherin's membrane anchors is necessary, and likely sufficient, to tether enveloped virus particles that bud through the plasma membrane.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                March 2012
                March 2012
                22 March 2012
                : 8
                : 3
                : e1002596
                Affiliations
                [1 ]Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America
                [2 ]Department of Microbiology, University of Colorado Denver, Aurora, Colorado, United States of America
                [3 ]Rocky Mountain Laboratories, National Institutes for Allergy and Infectious Diseases, National Institutes of Health (NIH), Hamilton, Montana, United States of America
                [4 ]Department of Immunology, University of Colorado Denver, Aurora, Colorado, United States of America
                Duke University Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: MLS BSB KJH. Performed the experiments: BSB MLS DSS SXL KG. Analyzed the data: MLS BSB KJH DSS SXL KG. Wrote the paper: MLS BSB KJH.

                Article
                PPATHOGENS-D-11-02698
                10.1371/journal.ppat.1002596
                3310811
                22457621
                ec9e2e36-fffb-4c8d-8ae8-de64af67df10
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                History
                : 8 December 2011
                : 1 February 2012
                Page count
                Pages: 13
                Categories
                Research Article
                Biology
                Genetics
                Microbiology

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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