title: Direct restriction of virus release and incorporation of the interferon-induced protein BST-2 into HIV-1 particles.
abstract: Investigation of the Vpu protein of HIV-1 recently uncovered a novel aspect of the mammalian innate response to enveloped viruses: retention of progeny virions on the surface of infected cells by the interferon-induced, transmembrane and GPI-anchored protein BST-2 (CD317; tetherin). BST-2 inhibits diverse families of enveloped viruses, but how it restricts viral release is unclear. Here, immuno-electron microscopic data indicate that BST-2 is positioned to directly retain nascent HIV virions on the plasma membrane of infected cells and is incorporated into virions. Virion-incorporation was confirmed by capture of infectivity using antibody to the ectodomain of BST-2. Consistent with a direct tethering mechanism, we confirmed that proteolysis releases restricted virions and further show that this removed the ectodomain of BST-2 from the cell surface. Unexpectedly, enzymatic cleavage of GPI anchors did not release restricted virions, weighing against models in which individual BST-2 molecules span the virion and host cell membranes. Although the exact molecular topology of restriction remains unsolved, we suggest that the incorporation of BST-2 into viral envelopes underlies its broad restrictive activity, whereas its relative exclusion from virions and sites of viral assembly by proteins such as HIV-1 Vpu may provide viral antagonism of restriction.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Fitzpatrick
authors.forename: Mark
authors.initials: M
authors.lastname: Skasko
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Deerinck
authors.forename: John
authors.initials: J
authors.lastname: Crum
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: John
authors.initials: J
authors.lastname: Guatelli
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004229:Dithiothreitol / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D058851:GPI-Linked Proteins; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D008854:Microscopy, Electron; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D014162:Transfection; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D014771:Virion / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D004229:Dithiothreitol; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D008562:Membrane Glycoproteins; D054801:Phosphoinositide Phospholipase C; D014759:Viral Envelope Proteins; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins