Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120.
The site on HIV-1 gp120 that binds to the CD4 receptor is vulnerable to antibodies. However, most antibodies that interact with this site cannot neutralize HIV-1. To understand the basis of this resistance, we determined co-crystal structures for two poorly neutralizing, CD4-binding site (CD4BS) antibodies, F105 and b13, in complexes with gp120. Both antibodies exhibited approach angles to gp120 similar to those of CD4 and a rare, broadly neutralizing CD4BS antibody, b12. Slight differences in recognition, however, resulted in substantial differences in F105- and b13-bound conformations relative to b12-bound gp120. Modeling and binding experiments revealed these conformations to be poorly compatible with the viral spike. This incompatibility, the consequence of slight differences in CD4BS recognition, renders HIV-1 resistant to all but the most accurately targeted antibodies.
Chen
Lei
L
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Kwon
Young Do
YD
Zhou
Tongqing
T
Wu
Xueling
X
O'Dell
Sijy
S
Cavacini
Lisa
L
Hessell
Ann J
AJ
Pancera
Marie
M
Tang
Min
M
Xu
Ling
L
Yang
Zhi-Yong
ZY
Zhang
Mei-Yun
MY
Arthos
James
J
Burton
Dennis R
DR
Dimitrov
Dimiter S
DS
Nabel
Gary J
GJ
Posner
Marshall R
MR
Sodroski
Joseph
J
Wyatt
Richard
R
Mascola
John R
JR
Kwong
Peter D
PD
D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D000939:Epitopes; D015483:HIV Antibodies / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D057131:Immune Evasion; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011487:Protein Conformation
D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; C514793:gp120 protein, Human immunodeficiency virus 1