Mutational pathways, resistance profile, and side effects of cyanovirin relative to human immunodeficiency virus type 1 strains with N-glycan deletions in their gp120 envelopes.
Limited data are available on the genotypic and phenotypic resistance profile of the alpha-(1-2)mannose oligomer-specific prokaryotic lectin cyanovirin (CV-N). Therefore, a more systematic investigation was carried out to obtain a better view of the interaction between CV-N and human immunodeficiency virus type 1 (HIV-1) gp120. When HIV-1-infected CEM cell cultures were exposed to CV-N in a dose-escalating manner, a total of eight different amino acid mutations exclusively located at N-glycosylation sites in the envelope surface gp120 were observed. Six of the eight mutations resulted in the deletion of high-mannose type N-glycans (i.e., at amino acid positions 230, 332, 339, 386, 392, and 448). Two mutations (i.e., at position 136 and 160) deleted a complex type N-glycan in the variable V1/V2 domain of gp120. The level of phenotypic resistance of the mutated virus strains against CV-N generally correlated with the number of glycan deletions in gp120, although deletion of the glycans at N-230, N-392, and N-448 generally afforded a more pronounced CV-N resistance than other N-glycan deletions. However, the extent of the decrease of antiviral activity of CV-N against the mutated virus strains was markedly less pronounced than observed for alpha(1-3)- and alpha(1-6)-mannose-specific plant lectins Hippeastrum hybrid agglutinin (HHA) and Galanthus nivalis agglutinin (GNA), which points to the existence of a higher genetic barrier for CV-N. This is in agreement with a more consistent suppression of a wider variety of HIV-1 clades by CV-N than by HHA and GNA. Whereas the antiviral and in vitro antiproliferative activity of CV-N can be efficiently reversed by mannan, the pronounced mitogenic activity of CV-N on peripheral blood mononuclear cells was unaffected by mannan, indicating that some of the observed side effects of CV-N are unrelated to its carbohydrate specificity/activity.
Balzarini
Jan
J
Rega Institute for Medical Research, KU Leuven, Belgium. jan.balzarini@rega.kuleuven.be
Van Laethem
Kristel
K
Peumans
Willy J
WJ
Van Damme
Els J M
EJ
Bolmstedt
Anders
A
Gago
Federico
F
Schols
Dominique
D
D001426:Bacterial Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D008958:Models, Molecular; D009154:Mutation; D011134:Polysaccharides / Q000737:chemistry / Q000235:genetics; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000821:virology
D001426:Bacterial Proteins; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D011134:Polysaccharides; C107733:cyanovirin N