Structural definition of a conserved neutralization epitope on HIV-1 gp120.
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.
Zhou
Tongqing
T
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Xu
Ling
L
Dey
Barna
B
Hessell
Ann J
AJ
Van Ryk
Donald
D
Xiang
Shi-Hua
SH
Yang
Xinzhen
X
Zhang
Mei-Yun
MY
Zwick
Michael B
MB
Arthos
James
J
Burton
Dennis R
DR
Dimitrov
Dimiter S
DS
Sodroski
Joseph
J
Wyatt
Richard
R
Nabel
Gary J
GJ
Kwong
Peter D
PD
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
D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120