Mycophenolic acid, an immunosuppressive agent, inhibits HBV replication invitro

Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid (MPA), is currently used as an immunosuppressive agent in kidney transplan t recipients. After oral administration, MMF is hydrolysed to MPA, the acti ve compound, which is a potent inhibitor of inosine monophosphate dehydroge nase (IMP-DH), Inhibition of this enzyme results in a depletion of the intr acellular GTP and dGTP pools. MPA has been shown to inhibit the replication of a number of viruses, including arena viruses (Junin and Tacaribe), yell ow fever virus, reovirus-1, parainfluenza-3 virus, Coxsackie B4 virus, Epst ein-Barr virus and human immunodeficiency virus. To examine whether MPA als o has an inhibitory effect on HBV replication, experiments were performed u sing cultures of primary human hepatocytes and HBV-transfected, HepG2 2.2.1 5 cells. After in vitro infection with HBV in human hepatocytes, HBV covale ntly-closed-circular (ccc) DNA and HBV mRNAs were detectable in the cells d uring the 10 days following infection, HBV DNA and hepatitis B surface anti gen (HBsAg) were also secreted into the culture medium. In the presence of 10 mu g ml(-1) MPA (the therapeutic serum level of MPA as an immunosuppress ive agent) in culture medium, HBV ccc DNA and HBV mRNAs became undetectable 5 days after treatment was started. The secretion of HBV DNA and HBsAg int o the medium was also markedly reduced, No cytotoxic effect of the drug was noted during the experiments. The effect of MPA on HBV replication was abo lished by the presence of guanosine (50 mu g ml(-1)). In HepG2 2.2.15 cells (which contain an integrated tandem dimer of the HBV genome), MPA treatmen t had no significant inhibitory effect on the secretion of HBV DNA and HBsA g into the culture medium. HBV ccc DNA and HBV mRNAs in HepG2 2.2.15 cells were also not affected. The observed effect of MPA on HBV replication in pr imary human hepatocyte cultures may involve only episomal replication and m ay have clinical implications, especially before integration of HBV DNA int o the host genome.