CT-2576, AN INHIBITOR OF PHOSPHOLIPID SIGNALING, SUPPRESSES CONSTITUTIVE AND INDUCED EXPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS

Viruses such as human immunodeficiency virus (HIV) require cellular ac tivation for expression. Cellular activation in lymphoid cells is asso ciated with augmented accumulation of certain phosphatidic acid (PA) s pecies derived from the hydrolysis of glycan phosphatidylinositol (GPI ). This suggests that activation of a phospholipid pathway may play a role in initiation of viral replication. To test this hypothesis, we e xamined the effect of tat gene expression on the production of cellula r PA species, as the Tat protein is essential for HIV expression and h as been implicated in activating the expression of multiple host cellu lar genes. Expression of tat increased the expression of PA. We then t ested whether synthetic inhibitors of PA metabolism would inhibit acti vation of the HIV long terminal repeat by Tat and tumor necrosis facto r alpha (TNF-alpha), CT-2576 suppressed both PA generation induced by Tat and HIV long terminal repeat-directed gene expression in response to Tat or TNF-alpha at a posttranscriptional step, CT-2576 also inhibi ted constitutive as well as TNF-alpha and interleukin 6-induced expres sion of HIV p24 antigen in chronically infected U1 cells and in periph eral blood lymphocytes acutely infected with a clinical isolate of HIV . Pharmacological inhibition of synthesis of selected PA species may t herefore provide a therapeutic approach to suppression of HIV replicat ion.