The long terminal repeats of human immunodeficiency virus type-1 and human T-cell leukemia virus type-I are activated by 12-O- tetradecanoylphorbol-13-acetate through different pathways

Abstract

The LTRs of HIV-1 and HTLV-1 have been shown by several laboratories to be activated by 12-O-tetradecanoylphorbol-13-acetate (TPA). This agent is a potent activator of protein kinase C (PKC). However, long exposure to TPA downregulates PKC in many cell types. We demonstrated that TPA treatment of Jurkat cells for more than 24 hr resulted in a sever depletion of this enzyme. Therefore, to explore the role of PKC in the effect of TPA on these LTRs, we transfected Jurkat cells with HIV-1 LTR-CAT or HTLV-1 LTR-CAT construct after 72 hr of TPA pretreatment. While this TPA pretreatment considerably reduced the HIV-1 LTR basal expression, it strongly stimulated the expression of HTLV-1 LTR. Furthermore, when TPA was added after transfection, a strong stimulation of HIV-1 LTR was observed, which could be abrogated by PKC inhibitors like H7 and chelerythryn. However, under these conditions TPA stimulated HTLV-1 LTR to a lesser extent than did the long- term TPA pretreatment. Moreover, this stimulation was enhanced by the PKC inhibitors. Thus our data indicate that while the effect of TPA on HIV-1 LTR is strictly dependent on PKC activity, its effect on HTLV-1 LTR is exerted via a different pathway that not only does not require PKC activation but rather seems to be antagonized by the activated PKC. Using a deletion mutant of HTLV-1 LTR we mapped the PKC-independent effect of TPA to the c-ets responsive region 1 (ERR-1) located in U3 of this LTR.