pyrimidinones and Liver-Cirrhosis--Biliary

Up to one-third of patients with primary biliary cirrhosis (PBC) experience recurrent disease following liver transplantation, which is associated with earlier and more severe recurrence in patients treated with tacrolimus as compared with cyclosporine A (CsA). As the latter has known antiviral activity, we hypothesized that CsA has the ability to inhibit the betaretrovirus characterized from patients with PBC.. We investigated whether CsA, the cyclosporine analogue NIM811, tacrolimus and other compounds can modulate the mouse mammary tumour virus production from Mm5MT cells. Viral load was evaluated in the cell supernatants by quantifying reverse transcriptase (RT) levels and betaretrovirus RNA.. A significant correlation was observed with increasing concentrations of CsA and NIM811, and decreasing of RT levels (rho-0.59, P=0.04 and rho-0.74, P=0.006 respectively), whereas tacrolimus had no significant effect (rho-0.27, P=0.4). At a dose of 3 microg/ml, CsA, NIM811 and the human immunodeficiency virus aspartyl protease inhibitor, lopinavir, were all associated with greater than three-fold reduction in the betaretrovirus RNA production from Mm5MT cells as compared with tacrolimus (P<0.005).. These studies demonstrate that the cyclophilin inhibitors CsA and NIM811 have antiviral activity against betaretrovirus production in vitro.

Topics: Animals; Antiviral Agents; Cell Line, Tumor; Cyclosporine; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Lopinavir; Mammary Tumor Virus, Mouse; Mice; Pyrimidinones; Recurrence; RNA-Directed DNA Polymerase; RNA, Viral; Tacrolimus; Viral Load; Virus Replication