Ritonavir Inhibits NF-AT Activation Through Effects on the PI-3 Kinase/Akt Pathway

The HIV protease inhibitor ritonavir has been reported to have activities unrelated to inhibition of HIV protease, including anti-tumor activity in vivo and in vitro, induction of lipodystrophy in vivo, inhibition of the 20S proteasome, and inhibition of NFkB activation. Here we show that ritonavir also inhibits activation of NF-AT by PMA plus ionomycin and by the HHV-8 vGPCR. Inhibition of NF-AT activation occurs through the PI-3 kinase/Akt/GSK-3 pathway, since ritonavir treatment leads to decreased Akt phosphorylation and a resultant decrease in GSK-3 phosphorylation. Treatment with ritonavir also inhibits the expression of NF-AT-dependent pro-inflammatory factors. Inhibition of multiple signaling pathways may help to explain the anti-tumor and other effects of ritonavir that are unrelated to its anti-retroviral activity.