title: Structural definition of a conserved neutralization epitope on HIV-1 gp120.
abstract: The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tongqing
authors.initials: T
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Barna
authors.initials: B
authors.lastname: Dey
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Hessell
authors.forename: Donald
authors.initials: D
authors.lastname: Van Ryk
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Xinzhen
authors.initials: X
authors.lastname: Yang
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Zhang
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zwick
authors.forename: James
authors.initials: J
authors.lastname: Arthos
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Richard
authors.initials: R
authors.lastname: Wyatt
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology* / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D008958:Models, Molecular; D008970:Molecular Weight; D009500:Neutralization Tests; D011487:Protein Conformation
chemical_list: D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120