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. 2005 Jun;79(12):7777-84.
doi: 10.1128/JVI.79.12.7777-7784.2005.

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

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Free PMC article

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

Myriam Witvrouw et al. J Virol. .
Free PMC article

Abstract

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.

Figures

FIG. 1.
FIG. 1.
Carbohydrate positions in gp120 proteins of HIV strains resistant to CV-N or ConA in comparison with those in gp120 of the HIV-1(NL4.3) strain. (A) Wild-type NL4.3; (B) NL4.3/CV-Nres; (C) NL4.3/ConAres.
FIG. 2.
FIG. 2.
Surface model of the core structure of HIV-1 gp120 (gray) bound to a ribbon diagram of CD4 (green). Deletion mutations (blue) in the V4 loop and point mutations (red) as a consequence of HIV resistance development to CV-N result in the loss of glycosylation sites in the gp120 envelope glycoprotein. The red arrow indicates the point mutation at residue 302 near the V3 loop that abolishes an important glycosylation site from the gp120 molecule.

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