NOVEL INDOLOCARBAZOLE PROTEIN-KINASE-C INHIBITORS PREVENT REACTIVATION OF HIV-1 IN LATENTLY INFECTED-CELLS

Suppression of human immunodeficiency virus-1 (HIV-1) reactivation in latently infected cells by protein kinase C (PKC) inhibitors has been described. Based on an initial finding with the indolocarbazole inhibi tor Go 6976 we have examined several members of this new class of pote nt and specific PKC inhibitors with respect to their ability to preven t the PKC-mediated induction of HIV-1 replication in the latently infe cted U1 cell line. Two of these compounds strongly inhibited not only PMA-induced release of p24-antigen and infectious virus particles into the supernatant (50% inhibition at 0.04-0.35 muM) but also TNF-alpha- mediated HIV-1 reactivation in the same concentration range. Significa nt lower toxicities compared to Go 6976 were observed for the new comp ounds, with 50% cytotoxic concentrations at 5.2 muM for Go 7775 and 3. 4 muM for Go 7716. This resulted in selectivity indices which were 10- 20-times higher compared to the reference compound Go 6976 and were co mparable to those of registered anti-AIDS drugs. No anti-HIV-1 activit y was observed for a closely related indolocarbazole analogue with no inhibitory activity in the PKC in vitro enzyme assay. This study demon strates the important role of PKC in reactivation of HIV-1 in latently infected cells and points to the potential of indolocarbazoles to pre serve the latent state of HIV-1 infection.