17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle

Magri, A. et al. (2017) 17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle. Liver International, 37(5), pp. 669-677. (doi: 10.1111/liv.13303) (PMID:27885811) (PMCID:PMC5448036)

Abstract

Rationale & Aim: Estrogen and estrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of HCV life cycle is/are affected by estrogens. Methods: Huh7 cells infected with the JFH1 virus (genotype 2a) were exposed to dehydroepiandrosterone, testosterone, progesterone and 17β-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate IC50 values. To dissect how 17β-estradiol interferes with phases of HCV life cycle, its effects were measured on the HCV pseudo-particle system (viral entry), the sub-genomic replicon N17/JFH1 and the replicon cell line Huh7-J17 (viral replication). Finally, in a dual-step infection model, infectious supernatants, collected from infected cells exposed to hormones, were used to infect naïve cells. Results: Progesterone and testosterone showed no inhibitory effect on HCV; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β-estradiol inhibited infection by 64-67% (IC50 values 140 to 160 nM). Fulvestrant reverted the inhibition by 17β-estradiol in a dose-dependent manner. 17β-estradiol exerted only a slight inhibition (<20%) on HCV pseudo-particles, and had no effect on cells either transiently or stably (Huh7-J17 cells) expressing the N17/JFH1 replicon. In the dual-step infection model, a significant IC50 decline occurred between primary (134 nM) and secondary (100 nM) infections (p=0.02), with extracellular HCV RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart. Conclusions: 17β-estradiol inhibits HCV acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the HCV life cycle.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cole, Ms Sarah and Patel, Professor Arvind and Magri, Mr Andrea
• Authors: Magri, A., Barbaglia, M. N., Foglia, C. Z., Boccato, E., Burlone, M. E., Cole, S., Giarda, P., Grossini, E., Patel, A. H., Minisini, R., and Pirisi, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Liver International
• Publisher: Wiley
• ISSN: 1478-3223
• ISSN (Online): 1478-3231
• Published Online: 07 November 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Liver International 37(5): 669-677
• Publisher Policy: Reproduced under a creative commons license

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
65649	1	Basis of the host range and tissue tropism for hepatitis C virus	Arvind Patel	Medical Research Council (MRC)	MC_UU_12014/2	MVLS III - CENTRE FOR VIRUS RESEARCH