ORGANIC THIOPHOSPHATE WR-151327 SUPPRESSES EXPRESSION OF HIV IN CHRONICALLY INFECTED-CELLS

Reducing agents such as glutathione (GSH), glutathione ester (GSE), an d 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 i nfected 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 col ony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-depende nt fashion, the reverse transcriptase (RT) activity induced by TNF-alp ha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, a nd 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot ana lysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in trans fected human rhabdomyosarcoma cells (RD). Suppression of HIV expressio n by WR-151327 was observed in the absence of a cytotoxic or cytostati c 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 induc e the expression of HIV. Our observations further support the hypothes is that reducing agents are important in the control of HIV replicatio n and that the clinical evaluation of WR-151327 may be indicated.