title: Paring Down HIV Env: Design and Crystal Structure of a Stabilized Inner Domain of HIV-1 gp120 Displaying a Major ADCC Target of the A32 Region.
abstract: Evidence supports a role of antibody-dependent cellular cytotoxicity (ADCC) toward transitional epitopes in the first and second constant (C1-C2) regions of gp120 (A32-like epitopes) in preventing HIV-1 infection and in vaccine-induced protection. Here, we describe the first successful attempt at isolating the inner domain (ID) of gp120 as an independent molecule that encapsulates the A32-like region within a minimal structural unit of the HIV-1 Env. Through structure-based design, we developed ID2, which consists of the ID expressed independently of the outer domain and stabilized in the CD4-bound conformation by an inter-layer disulfide bond. ID2 expresses C1-C2 epitopes in the context of CD4-triggered full-length gp120 but without any known neutralizing epitope present. Thus, ID2 represents a novel probe for the analysis and/or selective induction of antibody responses to the A32 epitope region. We also present the crystal structure of ID2 complexed with mAb A32, which defines its epitope.
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Tolbert
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Neelakshi
authors.initials: N
authors.lastname: Gohain
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, Montreal, 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, Université de Montréal, Montreal, 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: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Orlandi
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Visciano
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ebadi
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeVico
authors.affiliation: Profectus BioSciences, Inc., Baltimore, MD 21224, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Fouts
authors.affiliation: Centre de Recherche du CHUM, Université de Montréal, 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 H2X 0A9, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: George K
authors.initials: GK
authors.lastname: Lewis
authors.affiliation: Division of Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: mpazgier@ihv.umaryland.edu.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000737:chemistry*; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology; D062105:Molecular Docking Simulation
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1