title: Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity.
abstract: Human immunodeficiency virus type 1 (HIV-1) infection causes a progressive depletion of CD4 + T cells. Despite its importance for HIV-1 pathogenesis, the precise mechanisms underlying CD4 + T-cell depletion remain incompletely understood. Here we make the surprising observation that antibody-dependent cell-mediated cytotoxicity (ADCC) mediates the death of uninfected bystander CD4 + T cells in cultures of HIV-1-infected cells. While HIV-1-infected cells are protected from ADCC by the action of the viral Vpu and Nef proteins, uninfected bystander CD4 + T cells bind gp120 shed from productively infected cells and are efficiently recognized by ADCC-mediating antibodies. Thus, gp120 shedding represents a viral mechanism to divert ADCC responses towards uninfected bystander CD4 + T cells. Importantly, CD4-mimetic molecules redirect ADCC responses from uninfected bystander cells to HIV-1-infected cells; therefore, CD4-mimetic compounds might have therapeutic utility in new strategies aimed at specifically eliminating HIV-1-infected cells.
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors: Jonathan
authors: J
authors: Richard
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors: Maxime
authors: M
authors: Veillette
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors: Shilei
authors: S
authors: Ding
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors: Daria
authors: D
authors: Zoubchenok
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
authors: Nirmin
authors: N
authors: Alsahafi
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors: Mathieu
authors: M
authors: Coutu
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada.
authors: Nathalie
authors: N
authors: Brassard
authors: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors: Jongwoo
authors: J
authors: Park
authors: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors: Joel R
authors: JR
authors: Courter
authors: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors: Bruno
authors: B
authors: Melillo
authors: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors: Amos B
authors: AB
authors: Smith
authors: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
authors: George M
authors: GM
authors: Shaw
authors: Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
authors: Beatrice H
authors: BH
authors: Hahn
authors: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors: Joseph
authors: J
authors: Sodroski
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139-3583, USA; Department of Medicine, Université de Montréal, Montreal, QC H3C 3T5, Canada; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Daniel E
authors: DE
authors: Kaufmann
authors: Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: andres.finzi@umontreal.ca.
authors: Andrés
authors: A
authors: Finzi
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000821:virology*; D002450:Cell Communication; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018716:Molecular Mimicry; D011485:Protein Binding
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120
keywords: ADCC; Bystander killing; CD4; CD4-bound conformation; CD4-mimetics; Envelope glycoproteins; HIV-1; Non-neutralizing antibodies; gp120