The effect of substrates on the kinetics and the in vivo threshold activity of mutant HIV-1 proteases.

Abstract

The role of the human immunodeficiency virus (HIV) protease in the processing of gag and gag-pol polyproteins is essential for the maturation and the life cycle of the virus. The great potential of HIV protease as a therapeutic target for treating the acquired immunodeficiency syndrome, AIDS, has now been confirmed by the recent success of HIV inhibitor drugs to suppress HIV propagation in clinical trials (Ho et al, 1995; Wei et al., 1995; Coffin, 1995). In spite of the success, a serious problem associated with the clinical use of HIV protease inhibitor drugs is the rapid development of drug resistance by HIV. The basis of this drug resistance is the rapid propagation of HIV in the human body and the selection of resistance strains of the virus containing mutant proteases in the presence of inhibitor drugs (Coffin, 1995). The molecular basis of the resistance, therefore, resides on the properties of mutant proteases of the resistant HIV strains, which must have sufficient catalytic activity to support the viral propagation, yet a reduced sensitivity toward the inhibitors. This separate modulation of catalytic and inhibition activities in mutant HIV-1 proteases have now been demonstrated in many laboratories.