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Ritonavir inhibits NF-AT activation through modulation of the PI-3 kinase/Akt Ppathway

The HIV protease inhibitor ritonavir has activities apparently unrelated to its inhibition of the HIV protease, including anti-tumor activity in vivo and in vitro, induction of lipodystrophy in vivo, proteasome inhibition, and inhibition of NFκ. Here we show that ritonavir inhibits activation of NF-AT induced by PMA plus ionomycin and by the human herpes virus-8 chemokine receptor homologue, vGPCR. Inhibition occurred by modulation of the PI-3 kinase/Akt/GSK-3 pathway. Ritonavir treatment led to decreased Akt phosphorylation and a resultant decrease in GSK-3 phosphorylation and failed to inhibit NF-AT in GSK-3β -/- knockout cells. Inhibition of multiple signaling pathways by ritonavir may partly explain its anti-tumor activities as well as other effects of ritonavir that are unrelated to its anti-retroviral activity. Taken together, the data suggest that ritonavir may have intrinsic immunomodulatory activities. This work was supported in part by grant RO1 CA099905-01 from NCI.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Pati, S., Nguyen, A.T., Reid, W. et al. Ritonavir inhibits NF-AT activation through modulation of the PI-3 kinase/Akt Ppathway. Retrovirology 3 (Suppl 1), S68 (2006).

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