17β-estradiol inhibits the production of infectious particles of hepatitis C virus

Abstract

Persistent infection with hepatitis C virus causes serious liver diseases, such as chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma. The male gender is one of the critical factors in progression of hepatic fibrosis due to chronic HCV infection; thus female hormones may play a role in delaying the progression of hepatic fibrosis. It has also been reported that women are more likely than men to clear HCV in the acute phase of infection. These observations lead the present authors to the question: do female hormones inhibit HCV infection? In this study using HCV J6/JFH1 and Huh-7.5 cells, the possible inhibitory effect(s) of female hormones such as 17β-estradiol (the most potent physiological estrogen) and progesterone on HCV RNA replication, HCV protein synthesis and production of HCV infectious particles (virions) were analyzed. It was found that E₂, but not P₄, significantly inhibited production of the HCV virion without inhibiting HCV RNA replication or HCV protein synthesis. E₂-mediated inhibition of HCV virion production was abolished by a nuclear estrogen receptor (ER) antagonist ICI182780. Moreover, treatment with the ERα-selective agonist 4, 4', 4″- (4-propyl-[1H]-pyrazole-1, 3, 5-triyl)trisphenol (PPT), but not with the ERβ-selective agonist 2, 3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled receptor 30 (GPR30)-selective agonist 1-(4-[6-bromobenzo 1, 3 dioxol-5-yl]-3a, 4, 5, 9b-tetrahydro-3H-cyclopenta [c] quinolin-8-yl)-ethanone (G-1), significantly inhibited HCV virion production. Taken together, the present results suggest that the most potent physiological estrogen, E₂, inhibits the production of HCV infectious particles in an ERα-dependent manner.