Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes.
The conserved surfaces of the human immunodeficiency virus (HIV)-1 envelope involved in receptor binding represent potential targets for the development of entry inhibitors and neutralizing antibodies. Using structural information on a CD4-gp120-17b antibody complex, we have designed a 27-amino acid CD4 mimic, CD4M33, that presents optimal interactions with gp120 and binds to viral particles and diverse HIV-1 envelopes with CD4-like affinity. This mini-CD4 inhibits infection of both immortalized and primary cells by HIV-1, including primary patient isolates that are generally resistant to inhibition by soluble CD4. Furthermore, CD4M33 possesses functional properties of CD4, including the ability to unmask conserved neutralization epitopes of gp120 that are cryptic on the unbound glycoprotein. CD4M33 is a prototype of inhibitors of HIV-1 entry and, in complex with envelope proteins, a potential component of vaccine formulations, or a molecular target in phage display technology to develop broad-spectrum neutralizing antibodies.
Martin
Loïc
L
Department of Protein Engineering and Research, CEA Saclay, 91191 Gif-sur-Yvette, France.
Stricher
François
F
Missé
Dorothée
D
Sironi
Francesca
F
Pugnière
Martine
M
Barthe
Philippe
P
Prado-Gotor
Rafael
R
Freulon
Isabelle
I
Magne
Xavier
X
Roumestand
Christian
C
Ménez
André
A
Lusso
Paolo
P
Veas
Francisco
F
Vita
Claudio
C
D015704:CD4 Antigens / Q000737:chemistry* / Q000276:immunology*; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry* / Q000276:immunology; D006367:HeLa Cells / Q000737:chemistry / Q000276:immunology; D006801:Humans; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry* / Q000276:immunology*; D011487:Protein Conformation; D040901:Proteomics / Q000379:methods*; D011786:Quality Control; D020349:Surface Plasmon Resonance; D014771:Virion / Q000737:chemistry / Q000276:immunology
D015704:CD4 Antigens; C000607777:CD4M33 peptide; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D010455:Peptides