Selective estrogen receptor modulators inhibit hepatitis C virus infection at multiple steps of the virus life cycle

We screened for hepatitis C virus (HCV) inhibitors using the JFH-I viral culture system and found that selective estrogen receptor modulators (SERMs), such as tamoxifen, clomifene, raloxifene, and other estrogen receptor alpha (ER alpha)antagonists, inhibited HCV infection. Treatment with SERMs for the first 2 h and treatment 2-24 h after viral inoculation reduced the production of HCV RNA. Treating persistently JFH-1 infected cells with SERMs resulted in a preferential inhibition of extracellular HCV RNA compared to intracellular HCV RNA. When we treated two subgenomic replicon cells, which harbor HCV genome genotype 2a (JFH-1) or genotype lb, SERMs reduced HCV genome copies and viral protein NS5A. SERMs inhibited the entry of HCV pseudo-particle (HCVpp) genotypes la, lb, 2a, 2b and 4 but did not inhibit vesicular stomatitis virus (VSV) entry. Further experiment using HCVpp indicated that tamoxifen affected both viral binding to cell and post-binding events including endocytosis. Taken together, SERMs seemed to target multiple steps of HCV viral life cycle: attachment, entry, replication, and post replication events. SERMs may be potential candidates for the treatment of HCV infection. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.