Nature Biotechnology21, 71 - 76 (2002)
Published online: 16 December 2002; | doi:10.1038/nbt768
Rational design of a CD4 mimic that inhibits HIV-1 entry and exposes cryptic neutralization epitopes
Loïc Martin1, François Stricher1, Dorothée Missé2, Francesca Sironi3, Martine Pugnière4, Philippe Barthe5, Rafael Prado-Gotor5, Isabelle Freulon1, Xavier Magne2, Christian Roumestand5, André Ménez1, Paolo Lusso3, Francisco Veas2
& Claudio Vita1
1
Department of Protein Engineering and Research, CEA Saclay, 91191 Gif-sur-Yvette, France.
2
Retroviral and Molecular Immunology Laboratory, IRD/CNRS, 34094 Montpellier, France.
3
Unit of Human Virology, San Raffaele Scientific Institute, 20132 Milan, Italy.
4
Biotechnology and Pharmacology Institute, Faculty of Pharmacy, 34093 Montpellier, France.
5
Structural Biochemistry Center, Faculty of Pharmacy, 34093 Montpellier, France.
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.
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