CELL-BASED AND BIOCHEMICAL-ANALYSIS OF THE ANTI-HIV ACTIVITY OF COMBINATIONS OF 3'-AZIDO-3'-DEOXYTHYMIDINE AND ANALOGS OF TIBO

The toxicity of 3'-azido-3'-deoxythymidine (AZT) and the appearance of drug-resistant mutants in patients treated with AZT emphasizes the cr itical importance of the development of alternative strategies for the therapy of AIDS patients. Combination antiviral chemotherapy provides an attractive therapeutic strategy since the dose of the individual a gents may be lowered to reduce toxicity and the use of two potent anti viral agents may limit the development of drug resistance. Two analogu es of -imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO) potent ly and selectively inhibit the replication of HIV-1 in cell culture. I n combination with AZT, either of the two TIBO compounds, R82913 and R 86183, was highly synergistic in cell culture against HIV-1. However, in biochemical enzyme inhibition assays, utilizing recombinant HIV-1 r everse transcriptase, synergy was not detected at the enzymatic level. These results suggest that one of these two known inhibitors of HIV-1 reverse transcriptase may have a secondary mechanism of action distin ct from inhibition of the reverse transcriptase.