INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION BY SDZ-NIM-811, A NONIMMUNOSUPPRESSIVE CYCLOSPORINE ANALOG

(Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin whi ch is devoid of immunosuppressive activity but retains full capacity f or binding to cyclophilin and exhibits potent anti-human immunodeficie ncy virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HI V-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against lab oratory strains and against clinical isolates from geographically dist inct regions in primary T4 lymphocytes and in primary monocytes (50% i nhibitory concentration = 0.011 to 0.057 mu g/ml) was demonstrated. SD Z NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound do es not influence CD4 expression or inhibit fusion between virus-infect ed and uninfected cells. SDZ NIM 811 was, however, found to block form ation of infectious particles from chronically infected cells. Oral ad ministration to mice, rats, dogs, and monkeys resulted in levels in bl ood considerably exceeding the drug concentration, which completely bl ocked virus replication in primary cells. SDZ NIM 811 caused changes o f toxicity parameters in rats to a smaller degree than cyclosporine (f ormerly cyclosporin A). Thus, the potent and selective anti-HIV-l acti vity of SDZ NIM 811 and its favorable pharmacokinetic behavior togethe r with its lower nephrotoxicity than that of cyclosporine make this co mpound a promising candidate for development as an anti-HIV drug.