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Journal of Virology, June 2005, p. 7777-7784, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7777-7784.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Resistance of Human Immunodeficiency Virus Type 1 to the High-Mannose Binding Agents Cyanovirin N and Concanavalin A

Myriam Witvrouw,1,{dagger} Valery Fikkert,1,{dagger} Anke Hantson,1 Christophe Pannecouque,1 Barry R. O'Keefe,2 James McMahon,2 Leonidas Stamatatos,3 Erik de Clercq,1 and Anders Bolmstedt4,5*

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven, Belgium,1 Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland,2 Seattle Biomedical Research Institute and Department of Pathobiology, University of Washington, Seattle, Washington 98109,3 Centre for Microbiological Preparedness, Swedish Institute for Infectious Disease Control, Solna, Sweden,4 Goteborg University, Department of Clinical Virology, Goteborg, Sweden5

Received 27 April 2004/ Accepted 3 February 2005

Due to the biological significance of the carbohydrate component of the human immunodeficiency virus type 1 (HIV-1) glycoproteins in viral pathogenesis, the glycosylation step constitutes an attractive target for anti-HIV therapy. Cyanovirin N (CV-N), which specifically targets the high-mannose (HM) glycans on gp120, has been identified as a potent HIV-1 entry inhibitor. Concanavalin A (ConA) represents another mannose-binding lectin, although it has a lower specificity for HM glycans than that of CV-N. For the present study, we selected CV-N- and ConA-resistant HIV-1 strains in the presence of CV-N and ConA, respectively. Both resistant strains exhibited a variety of mutations eliminating N-linked glycans within gp120. Strains resistant to CV-N or ConA displayed high levels of cross-resistance towards one another. The N-glycan at position 302 was eliminated in both of the lectin-resistant strains. However, the elimination of this glycan alone by site-directed mutagenesis was not sufficient to render HIV-1 resistant to CV-N or ConA, suggesting that HIV-1 needs to mutate several N-glycans to become resistant to these lectins. Both strains also demonstrated clear cross-resistance towards the carbohydrate-dependent monoclonal antibody 2G12. In contrast, the selected strains did not show a reduced susceptibility towards the nonlectin entry inhibitors AMD3100 and enfuvirtide or towards reverse transcriptase or protease inhibitors. Recombination of the mutated gp160 genes of the strains resistant to CV-N or ConA into a wild-type background fully reproduced the (cross-)resistance profiles of the originally selected strains, pointing to the impact of the N-glycan mutations on the phenotypic resistance profiles of both selected strains.

* Corresponding author. Mailing address: Department of Clinical Virology, University of Göteborg, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden. Phone: 46 705 95 15 29. Fax: 46 31 82 70 32. E-mail: anders.bolmstedt{at}vgregion.se.

{dagger} Both authors contributed equally to this work.

Journal of Virology, June 2005, p. 7777-7784, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7777-7784.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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