Isolation of a Human Betaretrovirus from Patients with Primary Biliary Cholangitis.

A human betaretrovirus (HBRV) has been linked with the autoimmune liver disease, primary biliary cholangitis (PBC), and various cancers, including breast cancer and lymphoma. HBRV is closely related to the mouse mammary tumor virus, and represents the only exogenous betaretrovirus characterized in humans to date. Evidence of infection in patients with PBC has been demonstrated through the identification of proviral integration sites in lymphoid tissue, the major reservoir of infection, as well as biliary epithelium, which is the site of the disease process. Accordingly, we tested the hypothesis that patients with PBC harbor a transmissible betaretrovirus by co-cultivation of PBC patients' lymph node homogenates with the HS578T breast cancer line. Because of the low level of HBRV replication, betaretrovirus producing cells were subcloned to optimize viral isolation and production. Evidence of infection was provided by electron microscopy, RT-PCR, in situ hybridization, cloning of the HBRV proviral genome and demonstration of more than 3400 integration sites. Further evidence of viral transmissibility was demonstrated by infection of biliary epithelial cells. While HBRV did not show a preference for integration proximal to specific genomic features, analyses of common insertion sites revealed evidence of integration proximal to cancer associated genes. These studies demonstrate the isolation of HBRV with features similar to mouse mammary tumor virus and confirm that patients with PBC display evidence of a transmissible viral infection.

Cyclosporine A inhibits in vitro replication of betaretrovirus associated with primary biliary cirrhosis.

BACKGROUND/AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: These studies demonstrate that the cyclophilin inhibitors CsA and NIM811 have antiviral activity against betaretrovirus production in vitro.