The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding
Fischer PB, Collin M, Karlsson GB, James W, Butters TD, Davis SJ, Gordon S, Dwek RA, Platt FM. (1995), J Virol. 69, 5791-7
The alpha-glucosidase inhibitor N-butyldeoxynojirimycin (NB-DNJ) is a potent inhibitor of human immunodeficiency virus (HIV) replication and syncytium formation in vitro. However, the exact mechanism of action of NB-DNJ remains to be determined. In this study we have examined the impairment of HIV infectivity mediated by NB-DNJ. By two independent HIV entry assays [PCR-based HIV entry assay and entry of Cocal(HIV) pseudotypes], the reduction in infectivity was found to be due to an impairment of viral entry. No effect of NB-DNJ treatment was seen on the kinetics of the interaction between gp120 and CD4 (surface plasmon resonance; BIAcore) or on the binding of virus particles to H9 cells (using radiolabeled virions). We therefore conclude that a major mechanism of action of NB-DNJ as an inhibitor of HIV replication is the impairment of viral entry at the level of post-CD4 binding, due to an effect on viral envelope components.
Key figure: Effect of NB-DNJ treatment on the kinetics of the interaction between rshCD4 and rgp120
rgp120 was produced in either the presence or absence of 2 mM NB-DNJ. rshCD4 was generated in the absence of NB-DNJ. The kinetics were analyzed by surface plasmon resonance (BIAcore). Serial dilutions of rshCD4 were passed over two different flow cells containing rgp120 generated in the absence or presence of NB-DNJ immobilized to the matrix, and sensograms were recorded (A) (14 μg of rshCD4 per ml). Binding is measured in arbitrary response units (RU). Arrow 1 indicates the start of the injection of rshCD4, and arrow 2 indicates the end of the injection. A two-receptor model (A + B1 + B2 = AB1 + AB2) was fitted to the dissociation phases (B) and to the association phases (C), and one in every four datum points was plotted. The actual datum points are shown as symbols, and the fitted curves are shown as lines. The residuals from the fits are plotted below each of the association and dissociation phase plots.