GO-6976, A SELECTIVE INHIBITOR OF PROTEIN-KINASE-C, IS A POTENT ANTAGONIST OF HUMAN IMMUNODEFICIENCY VIRUS-1 INDUCTION FROM LATENT LOW-LEVEL-PRODUCING RESERVOIR CELLS-INVITRO

Human immunodeficiency virus (HIV-1) infection is followed by a period of latency or a low-level-persistent (LLP) state that results in an a symptomatic infection of the host. Productive viral expression may be triggered by a variety of activators including mitogens, antigens, and cytokines. Protein kinase C (PKC) has been shown to be important in t he intracellular cascade of signals induced by such activators. With U 1 and ACH-2 cell lines representative of an HIV-1 postintegration stat e, the effect of Go 6976, a synthetic inhibitor of PKC was tested. Go 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV- 1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleu kin 6. Go 6976 effectively blocks viral transcription induced by Bryos tatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Go 6976 als o blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Go 6976 shows a 12- to 60-fold more potent effe ct than for H-7, another PKC inhibitor with a similar mechanism. The i nhibitory effect is reduced when Go 6976 is not added before or within 1 hr of induction by the potent PKC activator Bryostatin 1. However, U1 cells can be grown for long periods in a nontoxic concentration of Go 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibitio n of HIV-1 proviral induction from latent/low-level-producing infectio us states with potent PKC inhibitors like Go 6976 may represent an add itional and promising antiviral approach.