Profile of resistance of human immunodeficiency virus to mannose-specific plant lectins.
The mannose-specific plant lectins from the Amaryllidaceae family (e.g., Hippeastrum sp. hybrid and Galanthus nivalis) inhibit human immunodeficiency virus (HIV) infection of human lymphocytic cells in the higher nanogram per milliliter range and suppress syncytium formation between persistently HIV type 1 (HIV-1)-infected cells and uninfected CD4(+) T cells. These lectins inhibit virus entry. When exposed to escalating concentrations of G. nivalis and Hippeastrum sp. hybrid agglutinin, a variety of HIV-1(III(B)) strains were isolated after 20 to 40 subcultivations which showed a decreased sensitivity to the plant lectins. Several amino acid changes in the envelope glycoprotein gp120, but not in gp41, of the mutant virus isolates were observed. The vast majority of the amino acid changes occurred at the N glycosylation sites and at the S or T residues that are part of the N glycosylation motif. The degree of resistance to the plant lectins was invariably correlated with an increasing number of mutated glycosylation sites in gp120. The nature of these mutations was entirely different from that of mutations that are known to appear in HIV-1 gp120 under the pressure of other viral entry inhibitors such as dextran sulfate, bicyclams (i.e., AMD3100), and chicoric acid, which also explains the lack of cross-resistance of plant lectin-resistant viruses to any other HIV inhibitor including T-20 and the blue-green algae (cyanobacteria)-derived mannose-specific cyanovirin. The plant lectins represent a well-defined class of anti-HIV (microbicidal) drugs with a novel HIV drug resistance profile different from those of other existing anti-HIV drugs.
Balzarini
Jan
J
Rega Institute for Medical Research, Gent, Belgium. jan.balzarini@rega.kuleuven.ac.be
Van Laethem
Kristel
K
Hatse
Sigrid
S
Vermeire
Kurt
K
De Clercq
Erik
E
Peumans
Willy
W
Van Damme
Els
E
Vandamme
Anne-Mieke
AM
Bölmstedt
Anders
A
Schols
Dominique
D
Böhlmstedt
Anders
A
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000494:pharmacology; D001596:Benzylamines; D002109:Caffeic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002460:Cell Line; D018920:Coculture Techniques; D000080027:Cyclams; D016264:Dextran Sulfate / Q000494:pharmacology; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015726:Giant Cells / Q000187:drug effects; D006031:Glycosylation; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D019668:Liliaceae / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology; D037121:Plant Lectins / Q000378:metabolism / Q000494:pharmacology*; D015728:Receptors, HIV / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D001426:Bacterial Proteins; D001596:Benzylamines; D002109:Caffeic Acids; D002352:Carrier Proteins; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D037121:Plant Lectins; D015728:Receptors, HIV; D013386:Succinates; C107733:cyanovirin N; D000077560:Enfuvirtide; D016264:Dextran Sulfate; C100435:chicoric acid; C088327:plerixafor