title: HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cells.
abstract: The type I interferon-inducible factor tetherin retains virus particles on the surfaces of cells infected with vpu-deficient human immunodeficiency virus type 1 (HIV-1). While this mechanism inhibits cell-free viral spread, the immunological implications of tethered virus have not been investigated. We found that surface tetherin expression increased the antibody opsonization of vpu-deficient HIV-infected cells. The absence of Vpu also stimulated NK cell-activating FcγRIIIa signaling and enhanced NK cell degranulation and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). The deletion of vpu in HIV-1-infected primary CD4(+) T cells enhanced the levels of antibody binding and Fc receptor signaling mediated by HIV-positive-patient-derived antibodies. The magnitudes of antibody binding and Fc signaling were both highly correlated to the levels of tetherin on the surfaces of infected primary CD4 T cells. The affinity of antibody binding to FcγRIIIa was also found to be critical in mediating efficient Fc activation. These studies implicate Vpu antagonism of tetherin as an ADCC evasion mechanism that prevents antibody-mediated clearance of virally infected cells.
  
  
  OBJECTIVE
  The ability of the HIV-1 accessory factor to antagonize tetherin has been considered to primarily function by limiting the spread of virus by preventing the release of cell-free virus. This study supports the hypothesis that a major function of Vpu is to decrease the recognition of infected cells by anti-HIV antibodies at the cell surface, thereby reducing recognition by antibody-dependent clearance by natural killer cells.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Alvarez
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Hamlin
authors.forename: Anthony
authors.initials: A
authors.lastname: Monroe
authors.forename: Brian
authors.initials: B
authors.lastname: Moldt
authors.forename: Mathew T
authors.initials: MT
authors.lastname: Hotta
authors.forename: Gabriela
authors.initials: G
authors.lastname: Rodriguez Caprio
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Fierer
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D009895:Opsonin Proteins / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D054334:Viral Regulatory and Accessory Proteins / Q000276:immunology*; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D052118:Lysosomal-Associated Membrane Protein 1; D009895:Opsonin Proteins; D017452:Receptors, IgG; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C496124:FCGR3A protein, human; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins