Inhibition of Human Immunodeficiency Virus Type 1 Replication in Acutely and Chronically Infected Cells by EM2487, a Novel Substance Produced by a Streptomyces Species

摘要: In a search for effective HIV-1 transcription inhibitors, we have evaluated more than 75,000 compounds their inhibitory effects on Tat-induced human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven reporter gene expression and found that EM2487, novel small-molecule substance produced by Streptomyces species, is potent selective inhibitor of replication in both acutely chronically infected cells. Its 50% concentration acute infection was 0.27 μM peripheral blood mononuclear cells (PBMCs), while the cytotoxic mock-infected PBMCs 13.3 μM. EM2487 proved to variety strains HIV-2 T-cell lines (MOLT-4 MT-4). The compound could suppress tumor necrosis factor alpha (TNF-α)-induced production latently (OM-10.1 ACH-2) as well constitutive viral (MOLT-4/IIIB U937/IIIB) without showing any cytotoxicity. did not affect early events cycle, determined proviral DNA synthesis MOLT-4 contrast, selectively prevented mRNA OM-10.1 cells, suggesting inhibition occurs at transcriptional level. Furthermore, inhibit TNF-α-induced LTR-driven but induced Tat, irrespective presence or absence nuclear κB binding sites LTR. These results suggest mechanism action attributable part Tat function.