Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1.
Anti-human immunodeficiency virus type 1 (HIV-1) antibodies whose binding to gp120 is enhanced by CD4 binding (CD4i antibodies) are generally considered nonneutralizing for primary HIV-1 isolates. However, a novel CD4i-specific Fab fragment, X5, has recently been found to neutralize a wide range of primary isolates. To investigate the precise nature of the extraordinary neutralizing ability of Fab X5, we evaluated the abilities of different forms (immunoglobulin G [IgG], Fab, and single-chain Fv) of X5 and other CD4i monoclonal antibodies to neutralize a range of primary HIV-1 isolates. Our results show that, for a number of isolates, the size of the neutralizing agent is inversely correlated with its ability to neutralize. Thus, the poor ability of CD4i-specific antibodies to neutralize primary isolates is due, at least in part, to steric factors that limit antibody access to the gp120 epitopes. Studies of temperature-regulated neutralization or fusion-arrested intermediates suggest that the steric effects are important in limiting the binding of IgG to the viral envelope glycoproteins after HIV-1 has engaged CD4 on the target cell membrane. The results identify hurdles in using CD4i epitopes as targets for antibody-mediated neutralization in vaccine design but also indicate that the CD4i regions could be efficiently targeted by small molecule entry inhibitors.
Labrijn
Aran F
AF
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Poignard
Pascal
P
Raja
Aarti
A
Zwick
Michael B
MB
Delgado
Karla
K
Franti
Michael
M
Binley
James
J
Vivona
Veronique
V
Grundner
Christoph
C
Huang
Chih-Chin
CC
Venturi
Miro
M
Petropoulos
Christos J
CJ
Wrin
Terri
T
Dimitrov
Dimiter S
DS
Robinson
James
J
Kwong
Peter D
PD
Wyatt
Richard T
RT
Sodroski
Joseph
J
Burton
Dennis R
DR
D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C055966:immunoglobulin Fv