title: Carbohydrate-binding agents cause deletions of highly conserved glycosylation sites in HIV GP120: a new therapeutic concept to hit the achilles heel of HIV.
abstract: 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 ( approximately 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. jan.balzarini@rega.kuleuven.be
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Willy
authors.initials: W
authors.lastname: Peumans
authors.forename: Els
authors.initials: E
authors.lastname: Van Damme
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D019380:Anti-HIV Agents; D001665:Binding Sites; D017124:Conserved Sequence; D024882:Drug Resistance, Viral; D005838:Genotype; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000502:physiology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D037102:Lectins / Q000494:pharmacology*; D037601:Mannose-Binding Lectin / Q000008:administration & dosage / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D037121:Plant Lectins / Q000494:pharmacology*; D011134:Polysaccharides / Q000032:analysis / Q000737:chemistry*; D026982:Urtica dioica / Q000737:chemistry; D014776:Virus Cultivation
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D037102:Lectins; D037601:Mannose-Binding Lectin; D037121:Plant Lectins; D011134:Polysaccharides