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Inhibition of the HIV-1 and HIV-2 proteases by a monoclonal antibody

Published online by Cambridge University Press:  01 December 1999

JULIEN LESCAR
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France ESRF, BP220, F-38043 Grenoble Cedex, France
JIRI BRYNDA
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
PAVLINA REZACOVA
Affiliation:
Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
RENATA STOURACOVA
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
MARIE-MADELEINE RIOTTOT
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France
VÉRONIQUE CHITARRA
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France
MILAN FABRY
Affiliation:
Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
MAGDA HOREJSI
Affiliation:
Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
JURAJ SEDLACEK
Affiliation:
Department of Gene Manipulation, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 37 Prague 6, Czech Republic
GRAHAM A. BENTLEY
Affiliation:
Unité d'Immunologie Structurale (URA 1961 CNRS), Département d'Immunologie, Institut Pasteur, 75724 Paris Cedex 15, France
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Abstract

The monoclonal antibody 1696, directed against the HIV-1 protease, displays strong inhibitory effects toward the catalytic activity of the enzyme of both the HIV-1 and HIV-2 isolates. This antibody cross-reacts with peptides that include the N-terminus of the enzyme, a region that is well conserved in sequence among different viral strains and which, furthermore, is crucial for homodimerization to the active enzymatic form. This observation, as well as antigen-binding studies in the presence of an active site inhibitor, suggest that 1696 inhibits the HIV protease by destabilizing its active homodimeric form. To characterize further how the antibody 1696 inhibits the HIV-1 and HIV-2 proteases, we have solved the crystal structure of its Fab fragment by molecular replacement and refined it at 3.0 Å resolution. The antigen binding site has a deep cavity at its center, which is lined mainly by acidic and hydrophobic residues, and is large enough to accommodate several antigen residues. The structure of the Fab 1696 could form a starting basis for the design of alternative HIV protease-inhibiting molecules of broad specificity.

Type
Research Article
Copyright
© 1999 The Protein Society

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