ACTIVITY OF TRICIRIBINE AND TRICIRIBINE-5'-MONOPHOSPHATE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND TYPE-2

Triciribine (TCN) and its 5'-monophosphate (TCN-P) are novel tricyclic compounds with known antitumor activity; TCN-P is currently in phase II human clinical trials. We now report that these compounds have pote nt and selective activity against HIV-1 and HIV-2. Using a syncytial p laque assay, TCN and TCN-P were active against HIV-1 at 0.01-0.02 muM and had differential selectivities of 2250 and 1900, respectively, com pared to 1850 for AZT. In contrast, TCN and TCN-P had minimal selectiv ity against human cytomegalovirus (50 and 27, respectively). TCN and T CN-P markedly inhibited HIV-1-induced p24 core antigen production, rev erse transcriptase, and infectious virus production in a dose-dependen t manner using HIV-1 acutely infected CEM-SS, H9, and persistently inf ected H9III(B) and U1 cells. In acutely infected PBL cells, TCN and TC N-P inhibited reverse transcriptase and infectious virus production bu t not p24 core antigen production. Using a microtiter XTT assay, TCN a nd TCN-P were active against a panel of HIV-1 and HIV-2 strains at IC5 0 values ranging from 0.02 to 0.46 muM. Evaluation of matched pairs of predrug and postdrug therapy HIV-1 isolates established that AZT-resi stant and TIBO-resistant variants of HIV-1 were sensitive to TCN or TC N-P. Furthermore, unlike AZT and other fraudulent nucleosides, neither TCN, TCN-P, nor TCN-TP inhibited the viral reverse transcriptase. Thu s, even though triciribine is a nucleoside chemically, it does not act biologically by classic nucleoside modalities but rather by a unique mechanism yet to be elucidated.