Dp. Merrill et al., ANTAGONISM BETWEEN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITORS INDINAVIR AND SAQUINAVIR IN-VITRO, The Journal of infectious diseases, 176(1), 1997, pp. 265-268
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.