Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01.
During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
Zhou
Tongqing
T
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Georgiev
Ivelin
I
Wu
Xueling
X
Yang
Zhi-Yong
ZY
Dai
Kaifan
K
Finzi
Andrés
A
Kwon
Young Do
YD
Scheid
Johannes F
JF
Shi
Wei
W
Xu
Ling
L
Yang
Yongping
Y
Zhu
Jiang
J
Nussenzweig
Michel C
MC
Sodroski
Joseph
J
Shapiro
Lawrence
L
Nabel
Gary J
GJ
Mascola
John R
JR
Kwong
Peter D
PD
D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology*; D000915:Antibody Affinity; D000940:Antigenic Variation; D001483:Base Sequence; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; C514793:gp120 protein, Human immunodeficiency virus 1