title: HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.
abstract: The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding. Because gp120-receptor interactions involve conformational reorganization, we measured the entropies of binding for 20 gp120-reactive antibodies. Here we show that recognition by receptor-binding-site antibodies induces conformational change. Correlation with neutralization potency and analysis of receptor-antibody thermodynamic cycles suggested a receptor-binding-site 'conformational masking' mechanism of neutralization escape. To understand how such an escape mechanism would be compatible with virus-receptor interactions, we tested a soluble dodecameric receptor molecule and found that it neutralized primary HIV-1 isolates with great potency, showing that simultaneous binding of viral envelope glycoproteins by multiple receptors creates sufficient avidity to compensate for such masking. Because this solution is available for cell-surface receptors but not for most antibodies, conformational masking enables HIV-1 to maintain receptor binding and simultaneously to resist neutralization.
authors.affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA. pdkwong@nih.gov
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Michael L
authors.initials: ML
authors.lastname: Doyle
authors.forename: David J
authors.initials: DJ
authors.lastname: Casper
authors.forename: Claudia
authors.initials: C
authors.lastname: Cicala
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Leavitt
authors.forename: Shahzad
authors.initials: S
authors.lastname: Majeed
authors.forename: Tavis D
authors.initials: TD
authors.lastname: Steenbeke
authors.forename: Miro
authors.initials: M
authors.lastname: Venturi
authors.forename: Irwin
authors.initials: I
authors.lastname: Chaiken
authors.forename: Michael
authors.initials: M
authors.lastname: Fung
authors.forename: Hermann
authors.initials: H
authors.lastname: Katinger
authors.forename: Paul W I H
authors.initials: PW
authors.lastname: Parren
authors.forename: James
authors.initials: J
authors.lastname: Robinson
authors.forename: Donald
authors.initials: D
authors.lastname: Van Ryk
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
authors.forename: James
authors.initials: J
authors.lastname: Arthos
mesh_terms: D000915:Antibody Affinity; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D002151:Calorimetry; D019277:Entropy; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009500:Neutralization Tests; D011487:Protein Conformation; 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