title: Gö 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 in vitro.
abstract: Human immunodeficiency virus (HIV-1) infection is followed by a period of latency or a low-level-persistent (LLP) state that results in an asymptomatic 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 the intracellular cascade of signals induced by such activators. With U1 and ACH-2 cell lines representative of an HIV-1 postintegration state, the effect of Gö 6976, a synthetic inhibitor of PKC was tested. Gö 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV-1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleukin 6. Gö 6976 effectively blocks viral transcription induced by Bryostatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Gö 6976 also blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Gö 6976 shows a 12- to 60-fold more potent effect than for H-7, another PKC inhibitor with a similar mechanism. The inhibitory effect is reduced when Gö 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 Gö 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibition of HIV-1 proviral induction from latent/low-level-producing infectious states with potent PKC inhibitors like Gö 6976 may represent an additional and promising antiviral approach.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, MD 21231-1001.
authors.forename: K A
authors.initials: KA
authors.lastname: Qatsha
authors.forename: C
authors.initials: C
authors.lastname: Rudolph
authors.forename: D
authors.initials: D
authors.lastname: Marmé
authors.forename: C
authors.initials: C
authors.lastname: Schächtele
authors.forename: W S
authors.initials: WS
authors.lastname: May
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054713:Bryostatins; D002227:Carbazoles / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development*; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012367:RNA, Viral / Q000096:biosynthesis; D012194:RNA-Directed DNA Polymerase / Q000096:biosynthesis; D012191:Retroviridae Proteins / Q000096:biosynthesis; D013449:Sulfonamides; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
chemical_list: D054713:Bryostatins; D002227:Carbazoles; D007211:Indoles; D007546:Isoquinolines; D007783:Lactones; D018942:Macrolides; D010879:Piperazines; D012367:RNA, Viral; D012191:Retroviridae Proteins; D013449:Sulfonamides; C081021:Go 6976; C046785:bryostatin 1; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011493:Protein Kinase C; D012194:RNA-Directed DNA Polymerase