Protease inhibitors: beyond anti-viral property

Purpose: Since Mycobacteria, both Mycobacterium tuberculosis (M.tb) and Mycobacterium avium complex (MAC), are among the most common opportunistic infections in HIV-infected patients, this study was designed to evaluate the inhibitory effect of commercially-available protease inhibitors (PIs) on MAC-induced NF-kB activation and consequent HIV-LTR (long terminal repeat) upregulation.

Methods: The U937 cell line was used for both transient transfection with NF-kB/LTR Luc constructs and infection with MAC. Transfected cells and MAC-infected cells were co-cultured in the absence and presence of various concentrations of PIs for 24h at 37°C. Co-cultured cells were subsequently lysed, and luciferase activity was measured.  

Results: MAC-infected cells co-cultured with NF-kB/LTR-transfected cells exerted significant an increase in luciferase activity. Of nine PIs tested, Nelfinavir (NFV), Lopinavir (LPV), Ritonavir (RTV), Saquinavir (SQV) and Tipranavir (TPV) showed dose-dependent inhibitory effect on NFκB activity. Among these PIs, NFV and LPV showed the most potent effect as they were effective at concentrations as low as 2.5μg/ml, while the inhibitory effect of RTV, SQV and TPV was present only at the highest concentration tested (20μg/ml). Four other PIs, Indinavir (IDV), Darunavir (DRV), APV (Amprenavir), and Atazanavir (ATV) failed to show any inhibitory effect even at the highest non-toxic concentrations.

Conclusion: To our knowledge this is the first study that compares all commercially available protease inhibitors with regard to their anti-inflammatory effect unrelated to their anti-retroviral properties. Studies of the anti-inflammatory and immunomodulatory properties of this family of drugs as well as other antiretrovirals will provide insights into alternative mechanisms of action that may be clinically important.