Acridone derivatives are selective inhibitors of HIV-1 replication in chronically infected cells

In our extensive screening of anti-HIV-l agents in chronically infected cel l lines, we have found acridone derivatives to be selective inhibitors of H IV-1 replication. Among the acridone derivatives, 1-hydroxy-10-methyl-9,10- dihydroacrid-9-one (RD6-5071) suppressed tumor necrosis factor (TNF)-alpha- induced HIV-1 expression in the latently infected cell line OM-10.1, UI, an d ACH-2. Its 50% effective concentration for HIV-I p24 antigen production w as 2.0 mu g/ml in OM-10.1 cells, while its 50% cytotoxic concentration was 18 mu g/ml. The compound also inhibited phorbol 12-myristate 13-acetate (PM A)-induced HIV-I expression in these cell lines. Furthermore, RD6-5071 was inhibitory to HIV-1 replication in acutely infected U937 and peripheral blo od mononuclear cells. The compound was found to suppress TNF-alpha-induced HIV-1 long terminal repeat-driven gene expression. An inhibition assay for protein kinase C (PKC) revealed that RD6-5071 could reduce the enzyme activ ity. Furthermore, the compound was a moderate inhibitor of PMA-induced nucl ear factor kappa B (NF-kappa B) activation, as determined by a gel mobility shift analysis. These results suggest that the acridone derivatives suppre ss HIV-1 replication at the transcriptional level primarily through a mecha nism of PKC inhibition. (C) 1999 Elsevier Science B.V. All rights reserved.