INHIBITION OF HIV-1 TAT-MEDIATED TRANSACTIVATION BY QUINACRINE AND CHLOROQUINE

The replication of human immunodeficiency virus type 1 (HIV-1) require s cellular components to interact with regulatory elements located in the long terminal repeat (LTR) as well as viral proteins Tat and Rev. Several well known signaling transduction inhibitors were tested to de termine their effects on the Tat-mediated transactivation using a tran sfection assay with the bacterial chloramphenicol acetyltransferase un der the control of the HIV-1 LTR. The protein kinase C inhibitors curc umin and staurosporine, but not a tyrosine kinase inhibitor herbimycin e A, inhibited Tat-mediated LTR-driven transactivation. Two antimalari al drugs quinacrine and chloroquine, that are also arachidonic acid me tabolism inhibitors, were found to inhibit the Tat-mediated LTR-driven gene expression. Another inhibitor of arachidonic acid metabolism 4-b romophenacyl bromide was also found to inhibit Tat-mediated gene expre ssion driven by HIV-1 LTR. However, the antimalarial drug quinine elic ited no effects on Tat-mediated transactivation. These results suggest that the anti-arachidonic acid metabolism properties of quinacrine an d chloroquine may be responsible for their ability to inhibit Tat-medi ated LTR-regulated gene expression. (C) 1996 Academic Press, Inc.