CASEIN KINASE-II IS A SELECTIVE TARGET OF HIV-1 TRANSCRIPTIONAL INHIBITORS

The identification of cellular factors that are required to complete v arious steps of the HIV-1 life cycle may lead to the development of ne w therapeutics. One key step, transcription from the integrated provir us, is inhibited by members of two distinct classes of compounds, the flavonoids and the benzothiophenes, via an unknown mechanism, possibly involving a cellular factor, A marked specificity toward inhibiting H IV-1 transcription is evidenced by the ability of drug-treated cells t o retain their proliferative and differentiation capabilities, In addi tion, the compounds do not impede the activation and function of the t ranscriptional factor NF-kappa B. Here we report on the identification of several cellular proteins that mediate the HIV-1 transcriptional i nhibitory property of the flavonoid chrysin, Chemical and immunologic analyses identified these cellular proteins as the individual subunits of casein kinase II (CKII), Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII, Bo th chrysin and the benzothiophenes inhibited human recombinant CKII en zymatic activity and showed competitive kinetics with respect to ATP, analogous to the classic CKII inhibitor 5,6-dichloro-1-beta-D-ribofura nosylbenzimidazole (DRB), Moreover, DRB potently inhibited HIV-1 expre ssion in chronically infected cells, CKII may regulate HIV-1 transcrip tion by phosphorylating cellular proteins involved in HIV-1 transactiv ation that contain multiple CKII phosphorylation consensus sequences.