title: Vaccine-induced HIV-1 envelope gp120 constant region 1-specific antibodies expose a CD4-inducible epitope and block the interaction of HIV-1 gp140 with galactosylceramide.
abstract: Mucosal epithelial cell surface galactosylceramide (Galcer) has been postulated to be a receptor for HIV-1 envelope (Env) interactions with mucosal epithelial cells. Disruption of the HIV-1 Env interaction with such alternate receptors could be one strategy to prevent HIV-1 entry through the mucosal barrier. To study antibody modulation of HIV-1 Env-Galcer interactions, we used Galcer-containing liposomes to assess whether natural- and vaccine-induced monoclonal antibodies can block HIV-1 Env binding to Galcer. HIV-1 Env gp140 proteins bound to Galcer liposomes with Kds (dissociation constants) in the nanomolar range. Several HIV-1 ALVAC/AIDSVAX vaccinee-derived monoclonal antibodies (MAbs) specific for the gp120 first constant (C1) region blocked Galcer binding of a transmitted/founder HIV-1 Env gp140. Among the C1-specific MAbs that showed Galcer blocking, the antibody-dependent cellular cytotoxicity-mediating CH38 IgG and its natural IgA isotype were the most potent blocking antibodies. C1-specific IgG monoclonal antibodies that blocked Env binding to Galcer induced upregulation of the gp120 CD4-inducible (CD4i) epitope bound by MAb 17B, demonstrating that a conformational change in gp120 may be required for Galcer blocking. However, the MAb 17B itself did not block Env-Galcer binding, suggesting that the C1 antibody-induced gp120 conformational changes resulted in alteration in a Galcer binding site distant from the CD4i 17B MAb binding site.
  
  
  OBJECTIVE
  Galactosyl ceramide, a glycosphingolipid, has been postulated to be a receptor for the HIV-1 envelope glycoprotein (Env) interaction with mucosal epithelial cells. Here, we have mimicked this interaction by using an artificial membrane containing synthetic Galcer and recombinant HIV-1 Env proteins to identify antibodies that would block the HIV-1 Env-Galcer interaction. Our study revealed that a class of vaccine-induced human antibodies potently blocks HIV-1 Env-Galcer binding by perturbing the HIV-1 Env conformation.
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: S Moses
authors.initials: SM
authors.lastname: Dennison
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Anasti
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Jaeger
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Shelley M
authors.initials: SM
authors.lastname: Stewart
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Pinghuang
authors.initials: P
authors.lastname: Liu
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Kunz
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Vandergrift
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Sallie
authors.initials: S
authors.lastname: Permar
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Mattia
authors.initials: M
authors.lastname: Bonsignori
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Tropical Hygiene, Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayaphan
authors.affiliation: Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttithum
authors.affiliation: Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Rerks-Ngarm
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA alam0004@mc.duke.edu hayne002@mc.duke.edu.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA alam0004@mc.duke.edu hayne002@mc.duke.edu.
authors.forename: S Munir
authors.initials: SM
authors.lastname: Alam
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001665:Binding Sites / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005699:Galactosylceramides / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008081:Liposomes / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; C112734:AIDSVAX; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D005699:Galactosylceramides; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; D008081:Liposomes; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1