Flavopiridol inhibits P-TEFb and blocks HIV-1 replication

Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibit or that is in clinical trials as a cancer treatment because of its antiprol iferative properties. We found that the flavonoid potently inhibited transc ription by RNA polymerase II in vitro by blocking the transition into produ ctive elongation, a step controlled by P-TEFb, The ability of P-TEFb to pho sphorylate the carboxyl-terminal domain of the large subunit of RNA polymer ase II was inhibited by flavopiridol with a K-i of 3 nM. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 i s a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat, Consistent with its ability to inhibit P-TEFb, flavop iridol blocked Tat transactivation of the viral promoter in vitro. Furtherm ore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC50 of less than 10 nM.