ANTAGONISM BETWEEN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITORS INDINAVIR AND SAQUINAVIR IN-VITRO

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors are a promising class of antiretroviral agents that compromise enzymatic fun ction through substrate mimicry. The in vitro susceptibility of a pane l of HIV-1 clinical isolates demonstrating various drug resistance phe notypes to combinations of the HIV-1 protease inhibitors saquinavir an d indinavir was determined. Antiviral effect was assessed by an HIV-1 p24 antigen reduction assay in phytohemagglutinin-stimulated periphera l blood mononuclear cells after harvesting of cell-free supernatant fl uids at peak antigen production (days 4-7). Drug interactions were det ermined by median-dose-effect analysis, with the combination index (CI ) calculated at several inhibitory concentrations (IC50, IC75, IC90, I C95, IC99). The interactive effects ranged from synergy at low efficac y doses to antagonism at higher doses against a pan-susceptible clinic al isolate of HIV-1. Against a zidovudine-resistant isolate as well as a multidrug-resistant isolate, the combination of saquinavir and indi navir demonstrated antagonism at all doses.