title: Cocrystal Structures of Antibody N60-i3 and Antibody JR4 in Complex with gp120 Define More Cluster A Epitopes Involved in Effective Antibody-Dependent Effector Function against HIV-1.
abstract: Accumulating evidence indicates a role for Fc receptor (FcR)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC), in prevention of human immunodeficiency virus type 1 (HIV-1) acquisition and in postinfection control of viremia. Consequently, an understanding of the molecular basis for Env epitopes that constitute effective ADCC targets is of fundamental interest for humoral anti-HIV-1 immunity and for HIV-1 vaccine design. A substantial portion of FcR effector function of potentially protective anti-HIV-1 antibodies is directed toward nonneutralizing, transitional, CD4-inducible (CD4i) epitopes associated with the gp41-reactive region of gp120 (cluster A epitopes). Our previous studies defined the A32-like epitope within the cluster A region and mapped it to the highly conserved and mobile layers 1 and 2 of the gp120 inner domain within the C1-C2 regions of gp120. Here, we elucidate additional cluster A epitope structures, including an A32-like epitope, recognized by human monoclonal antibody (MAb) N60-i3, and a hybrid A32-C11-like epitope, recognized by rhesus macaque MAb JR4. These studies define for the first time a hybrid A32-C11-like epitope and map it to elements of both the A32-like subregion and the seven-layered β-sheet of the gp41-interactive region of gp120. These studies provide additional evidence that effective antibody-dependent effector function in the cluster A region depends on precise epitope targeting--a combination of epitope footprint and mode of antibody attachment. All together these findings help further an understanding of how cluster A epitopes are targeted by humoral responses.
  
  
  OBJECTIVE
  HIV/AIDS has claimed the lives of over 30 million people. Although antiretroviral drugs can control viral replication, no vaccine has yet been developed to prevent the spread of the disease. Studies of natural HIV-1 infection, simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected nonhuman primates (NHPs), and HIV-1-infected humanized mouse models, passive transfer studies in infants born to HIV-infected mothers, and the RV144 clinical trial have linked FcR-mediated effector functions of anti-HIV-1 antibodies with postinfection control of viremia and/or blocking viral acquisition. With this report we provide additional definition of the molecular determinants for Env antigen engagement which lead to effective antibody-dependent effector function directed to the nonneutralizing CD4-dependent epitopes in the gp41-reactive region of gp120. These findings have important implications for the development of an effective HIV-1 vaccine.
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Neelakshi
authors.initials: N
authors.lastname: Gohain
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Tolbert
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tongyun
authors.initials: T
authors.lastname: Liu
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Pingsen
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Orlandi
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Visciano
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Kamin-Lewis
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA Medical Care Clinical Center, VA Maryland Health Care Center, Baltimore, Maryland, USA.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Sajadi
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: Department of Pediatrics, Tulane University Medical Center, New Orleans, Louisiana, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeVico
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Krishanu
authors.initials: K
authors.lastname: Ray
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, USA Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA mpazgier@ihv.umaryland.edu.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001666:Binding Sites, Antibody / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000648:ultrastructure*; D015700:HIV Envelope Protein gp41 / Q000276:immunology / Q000648:ultrastructure*; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011961:Receptors, Fc / Q000276:immunology; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000821:virology
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D011961:Receptors, Fc