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.