Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gpl60

THE envelope glycoprotein of human immunodeficiency virus (HIV) initiates infection 1 by mediating fusion of the viral envelope with the cell membrane. Fusion activity requires proteolytic cleavage of the gp160 protein into gp120 and gp41 at a site containing several arginine and lysine residues 2 . Activation at basic cleavage sites is observed with many membrane proteins of cellular and viral origin. We have recently found that the enzyme activating the haemagglutinin of fowl plague virus (FPV), an avian influenza virus, is furin 3 . Furin, a subtilisin-like eukaryotic endoprotease 4–6 , has a substrate specificity for the consensus amino-acid sequence Arg-X-Lys/Arg-Arg at the cleavage site 7 . We show here that the glycoprotein of HIV-1, which has the same protease recognition motif as the FPV haemagglutinin, is also activated by furin. Furthermore, we present evidence that peptidyl-chloromethyl ketones that have the Arg-X-Lys/Arg-Arg motif and which are specific inhibitors of furin 3 interfere with cleavage of the HIV glycoprotein and hence its activation and the formation of infectious virus particles.