Resistance of human immunodeficiency virus type 1 to the high-mannose binding agents cyanovirin N and concanavalin A.
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.
Witvrouw
Myriam
M
Department of Clinical Virology, University of Göteborg, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden.
Fikkert
Valery
V
Hantson
Anke
A
Pannecouque
Christophe
C
O'keefe
Barry R
BR
McMahon
James
J
Stamatatos
Leonidas
L
de Clercq
Erik
E
Bolmstedt
Anders
A
D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism* / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D003208:Concanavalin A / Q000378:metabolism / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019302:HIV Envelope Protein gp160 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008358:Mannose / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009154:Mutation
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D001426:Bacterial Proteins; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D003208:Concanavalin A; C107733:cyanovirin N; D008358:Mannose