Phorbol ester-mediated induction of HIV-1 from a chronically infected promonocyte clone: blockade by protein kinase inhibitors and relationship to tat-directed trans-activation.
Potent inhibitors of protein kinases C and A, including 1-(5 isoquinolinyl sulfonyl) 2-methyl piperazine (H7), staurosporine, and 2-aminopurine, depressed phorbol ester-induced HIV-1 virion production and HIV-specific transcripts by greater than 90% in chronically infected promonocytic cells. Suppression was dose-dependent and occurred at concentration that had little effect on cell growth. These effects appeared to be specific to activation of the PKC-diacylglycerol system. They did not alter IUdr-mediated induction of HIV. In addition, PMA enhancement of an HIV-LTR driven reporter gene was not blocked by H7 in the presence or absence of exogenous tat, at concentrations capable of inhibiting upregulation of virus at the cellular level. Insight into the biochemical mechanisms of these processes is critical to understanding interactions of HIV with the immune system, and may eventually uncover new therapeutic strategies.
Laurence
J
J
Department of Medicine, New York Hospital-Cornell Medical Center, NY 10021.
Sikder
S K
SK
Jhaveri
S
S
Salmon
J E
JE
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015075:2-Aminopurine / Q000494:pharmacology*; D000225:Adenine / Q000031:analogs & derivatives*; D000470:Alkaloids / Q000494:pharmacology*; D002460:Cell Line; D002999:Clone Cells; D015696:Gene Products, tat / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007065:Idoxuridine / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
D000470:Alkaloids; D015696:Gene Products, tat; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D015075:2-Aminopurine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019311:Staurosporine; D000225:Adenine; D007065:Idoxuridine; D013755:Tetradecanoylphorbol Acetate