Organic thiophosphate WR-151327 suppresses expression of HIV in chronically infected cells.
Reducing agents such as glutathione (GSH), glutathione ester (GSE), and N-acetylcysteine (NAC) have been shown to suppress the induction of HIV expression in chronically infected cells stimulated by cytokines. We present data which show the effects of the organic thiophosphate WR-151327 on the expression of latent HIV in U1 cells. The chronically infected promonocytic cell line U1 constitutively expresses low levels of HIV that can be increased by 13-phorbol 12-myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), and granulocyte/monocyte colony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-dependent fashion, the reverse transcriptase (RT) activity induced by TNF-alpha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, and 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot analysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in transfected human rhabdomyosarcoma cells (RD). Suppression of HIV expression by WR-151327 was observed in the absence of a cytotoxic or cytostatic effect. Incubation of WR-151327 with human recombinant TNF-alpha for 6 hr at 37 degrees C did not alter the capacity of TNF-alpha to induce the expression of HIV. Our observations further support the hypothesis that reducing agents are important in the control of HIV replication and that the clinical evaluation of WR-151327 may be indicated.
Kalebic
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Laboratory of Molecular Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Schein
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D004999:Amifostine / Q000031:analogs & derivatives / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects / Q000382:microbiology; D016207:Cytokines / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D016207:Cytokines; D009946:Organothiophosphorus Compounds; D013438:Sulfhydryl Compounds; C058704:3-(3-methylaminopropylamino)propylmercaptan; C048392:WR 151327; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D004999:Amifostine