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J. Biol. Chem., Vol. 280, Issue 49, 41005-41014, December 9, 2005

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Carbohydrate-binding Agents Cause Deletions of Highly Conserved Glycosylation Sites in HIV GP120

A NEW THERAPEUTIC CONCEPT TO HIT THE ACHILLES HEEL OF HIV^*

Jan Balzarini1, Kristel Van Laethem, Sigrid Hatse, Matheus Froeyen, Willy Peumans, Els Van Damme, and Dominique Schols

From the Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven and the Department of Molecular Biotechnology, Ghent University, B-9000 Ghent, Belgium

Mannose-binding proteins derived from several plants (i.e. Hippeastrum hybrid and Galanthus nivalis agglutinin) or prokaryotes (i.e. cyanovirin-N) inhibit human immunodeficiency virus (HIV) replication and select for drug-resistant viruses that show profound deletion of N-glycosylation sites in the GP120 envelope (Balzarini, J., Van Laethem, K., Hatse, S., Vermeire, K., De Clercq, E., Peumans, W., Van Damme, E., Vandamme, A.-M., Bolmstedt, A., and Schols, D. (2004) J. Virol. 78, 10617-10627; Balzarini, J., Van Laethem, K., Hatse, S., Froeyen, M., Van Damme, E., Bolmstedt, A., Peumans, W., De Clercq, E., and Schols, D. (2005) Mol. Pharmacol. 67, 1556-1565). Here we demonstrated that the N-acetylglucosamine-binding protein from Urtica dioica (UDA) prevents HIV entry and eventually selects for viruses in which conserved N-glycosylation sites in GP120 were deleted. In contrast to the mannose-binding proteins, which have a 50-100-fold decreased antiviral activity against the UDA-exposed mutant viruses, UDA has decreased anti-HIV activity to a very limited extent, even against those mutant virus strains that lack at least 9 of 22 (40%) glycosylation sites in their GP120 envelope. Therefore, UDA represents the prototype of a new conceptual class of carbohydrate-binding agents with an unusually specific and targeted drug resistance profile. It forces HIV to escape drug pressure by deleting the indispensable glycans on its GP120, thereby obligatorily exposing previously hidden immunogenic epitopes on its envelope.

Received for publication, August 10, 2005 , and in revised form, September 7, 2005.

^* This work was supported by the European Commission, René Descartes Prize-2001, Krediet HPAW-2002-90001, and EMPRO 503558 of the 6th Framework Programme, the ANRS (France), the Fonds voor Wetenschappelijk Onderzoek Krediet G-0267-04, and the Centers of Excellence of the Katholieke Universiteit at Leuven Krediet EF/05/015. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Rega Institute for Medical Research, Katholieke Universiteit at Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Tel.: 32-16-337352; Fax: 32-16-337340; E-mail: jan.balzarini{at}rega.kuleuven.be.

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