Alisporivir Inhibition of Hepatocyte Cyclophilins Reduces HBV Replication and Hepatitis B Surface Antigen Production.pdfVIP

Gastroenterology 2015;148:403–414 Alisporivir Inhibition of Hepatocyte Cyclophilins Reduces HBV Replication and Hepatitis B Surface Antigen Production Sandra Phillips,1,* Shilpa Chokshi,1,* Udayan Chatterji,2 Antonio Riva,1 Michael Bobardt,2 Roger Williams,1 Philippe Gallay,2 and Nikolai V. Naoumov3 1Institute of Hepatology, Foundation for Liver Research, London, United Kingdom; 2Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California; and 3Novartis Pharma AG, Basel, Switzerland BACKGROUND AIMS: Cyclophilins are host factors required and CYPC reside in the lumen of the endoplasmic reticulum, for hepatitis C virus replication. Cyclophilin inhibitors such as CYPD is present in the mitochondria, and CYPE is localized alisporivir have shown strong anti–hepatitis C virus activity in the nucleus. in vitro and in clinical studies. However, little is known about Cyclophilins are involved in the life cycle of a wide range whether hepatocyte cyclophilins are involved in the hepatitis B of viruses including hepatitis C virus (HCV), human immu- virus (HBV) life cycle. We investigated the effects of 2 cyclo- nodeficiency virus, vaccinia virus, coronaviruses, and poly- philin inhibitors (alisporivir and NIM811) on HBV replication omavirus BK, acting as host co-factors essential for virus and hepatitis B surface antigen (HBsAg) production in cell lines. replication.3–8 CYPA is the main cyclophilin that is involved METHODS: Liver-derived cell lines producing full-length HBV directly in the life cycle of HCV2–4 and inhibition of its and HBsAg particles, owing to stable (HepG2215) or transient peptidyl-prolyl isome