1. 17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle.
- Author
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Magri A, Barbaglia MN, Foglia CZ, Boccato E, Burlone ME, Cole S, Giarda P, Grossini E, Patel AH, Minisini R, and Pirisi M
- Subjects
- Cell Line, Hepacivirus genetics, Hepatitis C drug therapy, Humans, Progesterone pharmacology, RNA, Viral drug effects, Replicon drug effects, Testosterone pharmacology, Virus Internalization drug effects, Estradiol pharmacology, Estrogens pharmacology, Hepacivirus drug effects, Hepacivirus physiology, Virus Replication drug effects
- Abstract
Background & Aims: Oestrogen and oestrogen-mediated signalling protect from hepatitis C virus through incompletely understood mechanisms. We aimed to ascertain which phase(s) of hepatitis C virus life cycle is/are affected by oestrogens., 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 half maximal inhibitory concentration values. To dissect how 17β-estradiol interferes with phases of hepatitis C virus life cycle, its effects were measured on the hepatitis C virus pseudo-particle system (viral entry), the subgenomic 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 hepatitis C virus; dehydroepiandrosterone was only mildly inhibitory. In contrast, 17β-estradiol inhibited infection by 64%-67% (IC
50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17β-estradiol in a dose-dependent manner. 17β-estradiol exerted only a slight inhibition (<20%) on hepatitis C virus 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 half maximal inhibitory concentration decline occurred between primary (134 nmol/L) and secondary (100 nmol/L) infections (P=.02), with extracellular hepatitis C virus RNA and infectivity being reduced to a higher degree in comparison to its intracellular counterpart., Conclusions: 17β-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2017
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