HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.
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.
Kwong
Peter D
PD
Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA. pdkwong@nih.gov
Doyle
Michael L
ML
Casper
David J
DJ
Cicala
Claudia
C
Leavitt
Stephanie A
SA
Majeed
Shahzad
S
Steenbeke
Tavis D
TD
Venturi
Miro
M
Chaiken
Irwin
I
Fung
Michael
M
Katinger
Hermann
H
Parren
Paul W I H
PW
Robinson
James
J
Van Ryk
Donald
D
Wang
Liping
L
Burton
Dennis R
DR
Freire
Ernesto
E
Wyatt
Richard
R
Sodroski
Joseph
J
Hendrickson
Wayne A
WA
Arthos
James
J
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*
D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015728:Receptors, HIV