title: Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1.
abstract: Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Aran F
authors.initials: AF
authors.lastname: Labrijn
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Aarti
authors.initials: A
authors.lastname: Raja
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.forename: Karla
authors.initials: K
authors.lastname: Delgado
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
authors.forename: James
authors.initials: J
authors.lastname: Binley
authors.forename: Veronique
authors.initials: V
authors.lastname: Vivona
authors.forename: Christoph
authors.initials: C
authors.lastname: Grundner
authors.forename: Chih-Chin
authors.initials: CC
authors.lastname: Huang
authors.forename: Miro
authors.initials: M
authors.lastname: Venturi
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C055966:immunoglobulin Fv