12th International HIV Drug Resistance Workshop


10–14 June 2003, Cabo del Sol, Los Cabos, Mexico


IN VITRO RESISTANCE DEVELOPMENT OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 TOWARDS MANNOSE-SPECIFIC PLANT LECTINS

Antivir Ther. 2003; 8:S29 (abstract no. 26)

K Van Laethem1,2, Y Schrooten1,2, S Hatse1, K Vermeire1, E De Clercq1, W Peumans3, E Van Damme4, D Schols1, A-M Vandamme1,2 and J Balzarini1
1Rega Institute for Medical Research, Katholieke Universiteit Leuven; 2AIDS Reference Laboratory, University Hospitals Leuven; 3Department of Fytopathology, Katholieke Universiteit Leuven; and 4Department of Molecular Biotechnology, Rijksuniversiteit Gent, Belgium

BACKGROUND: Mannose-specific plant lectins from the Amaryllidaceae family, such as Galanthus nivalis agglutinin (GNA) and Hippeastrum hybrid agglutinin (HHA), have previously been shown to exhibit pronounced anti-HIV activity (Balzarini et al., Antimicrob Agents Chemother. 1991 Mar;35(3):410-6). There is strong evidence that these drugs target the heavily glycosylated envelope glycoprotein gp120. Therefore, the aim of this study was to select for resistance against GNA and HHA, to determine the phenotype and the associated genotypic changes in the HIV envelope gene.

METHODS: HIV-1 was subjected to sub-cultivations in the presence of dose-escalating concentrations of GNA and HHA. Virus isolates, recovered in the presence of different concentrations of the respective drugs, were investigated for their phenotypic susceptibility towards a subset of mannose-specific plant lectins, and a variety of viral entry and reverse transcriptase inhibitors. Their gp120 and gp41 gene sequences were also determined.

RESULTS: Many sub-cultivation steps were required to obtain virus strains that could grow in the presence of drug concentrations that were at least 100-fold higher than the initial EC50 (50% effective concentration) values. The mutations found in the different virus isolates were predominantly related to N-glycosylation sites and at the S or T residues that are part of the Nglycosylation motif. One potential O-glycosylation site in gp120 was also affected. The degree of resistance of HIV-1 to the plant lectins was correlated with an increasing number of mutated glycosylation sites in gp120. The susceptibility of the GNA- and HHA-resistant virus strains towards other viral entry and RT inhibitors was fully preserved.

CONCLUSIONS: Resistance development of HIV-1 against the mannose-specific plant lectins GNA and HHA is associated with a unique spectrum of resistance mutations in the gp120 envelope gene, which has not been previously observed with any of the other known viral entry inhibitors.

PRESENTING AUTHOR: K Van Laethem

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2003-07-08
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