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      Cell-to-cell transmission of retroviruses: Innate immunity and interferon-induced restriction factors

      review-article
      *
      Virology
      Academic Press
      HIV, Retrovirus, Virological synapse, Restriction factor, Innate immunity, Interferon, Tetherin, BST-2, Vpu

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          Abstract

          It has been known for some time that retroviruses can disseminate between immune cells either by conventional cell-free transmission or by directed cell-to-cell spread. Over the past few years there has been increasing interest in how retroviruses may use cell-to-cell spread to promote more rapid infection kinetics and circumvent humoral immunity. Effective humoral immune responses are intimately linked with innate immunity and the interplay between retroviruses and innate immunity is a rapidly expanding area of research that has been advanced considerably by the identification of cellular restriction factors that provide barriers to retroviral infection. The effect of innate immunity and restriction factors on retroviral cell-to-cell spread has been comparatively little studied; however recent work suggests this maybe changing. Here I will review some recent advances in what is a budding area of retroviral research.

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          Most cited references128

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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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              Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8.

              F Heil (2004)
              Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.
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                Author and article information

                Journal
                Virology
                Virology
                Virology
                Academic Press
                0042-6822
                1096-0341
                15 March 2011
                15 March 2011
                : 411
                : 2
                : 251-259
                Affiliations
                Wohl Virion Centre and MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, W1T 4JF, UK
                Author notes
                [* ]Fax: +44 207 679 9555. c.jolly@ 123456ucl.ac.uk
                Article
                YVIRO6040
                10.1016/j.virol.2010.12.031
                3053447
                21247613
                f77ca0d4-7583-437c-9793-62f875081c1c
                © 2011 Elsevier Inc.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 10 December 2010
                : 13 December 2010
                : 17 December 2010
                Categories
                Review

                Microbiology & Virology
                vpu,retrovirus,bst-2,tetherin,virological synapse,hiv,restriction factor,innate immunity,interferon

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