P53 TRANSACTIVATION OF THE HIV-1 LONG TERMINAL REPEAT IS BLOCKED BY PD-144795, A CALCINEURIN-INHIBITOR WITH ANTI-HIV PROPERTIES

Previous reports have indicated that benzothiophenes exhibit broad ant i-inflammatory properties and inhibit human immunodeficiency virus-typ e 1 (HIV-1) replication. We show that the immunosuppressant cyclospori n A (CsA) and benzothiophene-2-carboxamide, 5-methoxy-3-(1-methyl etho xy)-1-oxide (PD 144795) block the induction of p53 and NF-kappa B bind ing to the HIV-1 long terminal repeat (LTR) by the T cell receptor act ivator phytohemagglutinin. CsA and PD 144795 also inhibit the inductio n by phytohemagglutinin of the transcription mediated by an HIV-1 LTR fragment containing the p53 and NF-kappa B sites. These effects of PD 144795 on HIV-1 transcription correlate with its ability to inhibit th e phosphatase activity of calcineurin and are similar to those previou sly described for CsA. Moreover, a constitutive active form of calcine urin is able to induce expression from the HIV-1 LTR in a p53- and NF- kappa B-dependent manner and PD 144795 is able to block this induction . These results demonstrate that the DNA binding of p53 to the HIV-1 L TR can be modulated by calcineurin and provide a framework to understa nd the anti-HIV properties of benzothiophene derivatives.