title: Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins.
abstract: Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to "push" Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. Here we test whether CD4mc also expose epitopes recognized by anti-cluster A monoclonal antibodies such as A32, thought to be responsible for the majority of ADCC activity present in HIV+ sera and linked to decreased HIV-1 transmission in the RV144 trial. We made the surprising observation that CD4mc are unable to enhance recognition of HIV-1-infected cells by this family of antibodies in the absence of antibodies such as 17b, which binds a highly conserved CD4-induced epitope overlapping the co-receptor binding site (CoRBS). Our results indicate that CD4mc initially open the trimeric Env enough to allow the binding of CoRBS antibodies but not anti-cluster A antibodies. CoRBS antibody binding further opens the trimeric Env, allowing anti-cluster A antibody interaction and sensitization of infected cells to ADCC. Therefore, ADCC responses mediated by cluster A antibodies in HIV-positive sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells. The understanding of the conformational changes required to expose these vulnerable Env epitopes might be important in the design of new strategies aimed at fighting HIV-1.
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada. Electronic address: jonathan.richard.1@umontreal.ca.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Richard
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pacheco
authors.affiliation: Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Neelakshi
authors.initials: N
authors.lastname: Gohain
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Veillette
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Nirmin
authors.initials: N
authors.lastname: Alsahafi
authors.affiliation: Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Tolbert
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Prévost
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Chapleau
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coutu
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY, USA.
authors.forename: Manxue
authors.initials: M
authors.lastname: Jia
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brassard
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors.forename: Jongwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Courter
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Melillo
authors.affiliation: CEA, iBiTecS, Service d'Ingénierie Moléculaire des Protéines, Gif sur Yvette, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.affiliation: Centre de Recherche du CHUM, QC H2X 0A9, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada.
authors.forename: Cécile
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6076, USA.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Centre de Recherche du CHUM, 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.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of the Rockefeller University, New York, NY, USA.
authors.forename: Xueling
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 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.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.affiliation: Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.affiliation: Centre de Recherche du CHUM, 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.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D000595:Amino Acid Sequence; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D001665:Binding Sites; D000067558:Biological Mimicry; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D017124:Conserved Sequence; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D011485:Protein Binding / Q000276:immunology; D015728:Receptors, HIV / Q000737:chemistry / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015728:Receptors, HIV
keywords: ADCC; CD4; CD4-mimetics; Envelope glycoproteins; HIV-1; Non-neutralizing antibodies