title: 17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle.
abstract: 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.
  
  
  
  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.
  
  
  
  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% (IC50values 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.
  
  
  
  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.
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.|MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magri
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Matteo N
authors.initials: MN
authors.lastname: Barbaglia
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Chiara Z
authors.initials: CZ
authors.lastname: Foglia
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Boccato
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.|CRRF Mons. Luigi Novarese, Moncrivello, Vercelli, Italy.
authors.forename: Michela E
authors.initials: ME
authors.lastname: Burlone
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cole
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Giarda
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Grossini
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Glasgow, UK.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Rosalba
authors.identifier: 0000-0002-7548-9731
authors.initials: R
authors.lastname: Minisini
authors.affiliation: Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Pirisi
mesh_terms: D002460:Cell Line; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D011374:Progesterone / Q000494:pharmacology; D012367:RNA, Viral / Q000187:drug effects; D012093:Replicon / Q000187:drug effects; D013739:Testosterone / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D004967:Estrogens; D012367:RNA, Viral; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol
keywords: 17β-estradiol; antivirals; hepatitis C virus; oestrogen