Broadly cross-reactive HIV-1-neutralizing human monoclonal Fab selected for binding to gp120-CD4-CCR5 complexes.
HIV-1 entry into cells involves formation of a complex between gp120 of the viral envelope glycoprotein (Env), a receptor (CD4), and a coreceptor, typically CCR5. Here we provide evidence that purified gp120(JR-FL)-CD4-CCR5 complexes exhibit an epitope recognized by a Fab (X5) obtained by selection of a phage display library from a seropositive donor with a relatively high broadly neutralizing serum antibody titer against an immobilized form of the trimolecular complex. X5 bound with high (nM) affinity to a variety of Envs, including primary isolates from different clades and Envs with deleted variable loops (V1, -2, -3). Its binding was significantly increased by CD4 and slightly enhanced by CCR5. X5 inhibited infection of peripheral blood mononuclear cells by a selection of representative HIV-1 primary isolates from clades A, B, C, D, E, F, and G with an efficiency comparable to that of the broadly neutralizing antibody IgG1 b12. Furthermore, X5 inhibited cell fusion mediated by Envs from R5, X4, and R5X4 viruses. Of the five broadly cross-reactive HIV-1-neutralizing human monoclonal antibodies known to date, X5 is the only one that exhibits increased binding to gp120 complexed with receptors. These findings suggest that X5 could possibly be used as entry inhibitor alone or in combination with other antiretroviral drugs for the treatment of HIV-1-infected individuals, provide evidence for the existence of conserved receptor-inducible gp120 epitopes that can serve as targets for potent broadly cross-reactive neutralizing antibodies in HIV-1-infected patients, and have important conceptual and practical implications for the development of vaccines and inhibitors.
Moulard
Maxime
M
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Phogat
Sanjay K
SK
Shu
Yuuei
Y
Labrijn
Aran F
AF
Xiao
Xiaodong
X
Binley
James M
JM
Zhang
Mei-Yun
MY
Sidorov
Igor A
IA
Broder
Christopher C
CC
Robinson
James
J
Parren
Paul W H I
PW
Burton
Dennis R
DR
Dimitrov
Dimiter S
DS
D000911:Antibodies, Monoclonal / Q000276:immunology; D000915:Antibody Affinity; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000276:immunology*; D002459:Cell Fusion; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D003429:Cross Reactions; D015686:Gene Products, env / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D009500:Neutralization Tests; D019151:Peptide Library; D019713:Receptors, CCR5 / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015686:Gene Products, env; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1