SYNERGISTIC INHIBITION OF HIV-1 REVERSE-TRANSCRIPTASE AND HIV-1 REPLICATION BY COMBINING TROVIRDINE WITH AZT, DDL AND DDC IN-VITRO

Trovirdine (LY300046 . HCl) is a potent and selective non-nucleoside h uman immunodeficiency Virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor (Ahgren et al., Antimicrob Ag Chemother 39: 1329, 1995). Com binations of trovirdine with other RT inhibitors, ATT, ddC, ddl and th eir triphosphates, were studied as well as the pyrophosphate analogue PFA in both cell-free HIV-1 polymerase assays and HIV-1-infected MT-4 cell cultures, Synergistic effects and weak synergism were observed bo th using RT and HIV-1-infected cells and using different HIV-1 RT muta nts and HIV-1 drug-resistant variants known to be resistant to the inh ibitory effects of trovirdine. The best combination with substantial s ynergism was ddC-TP and trovirdine at a 20:1 molar ratio combination i n a cell-free enzyme assay, This combination showed the weak synergy i n MT-4 cells. Synergism was judged by the median-effect method. The in hibitory effect of trovirdine was independent of increased concentrati ons of ATT triphosphate and ddC triphosphate implying that trovirdine acts in a mutually exclusive manner with AZT-TP and ddC-TP as determin ed by the Dixon plot, The combination effects were expressed by the co mbination index (CI) using end points of 50%, 70% and 90% inhibition o f HIV-1 RT activity and HIV-1 replication in MT-4 cells.