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

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 17ß-estradiol (tested with/without its receptor antagonist fulvestrant). Dose-response curves were established to calculate half maximal inhibitory concentration values. To dissect how 17ß-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, 17ß-estradiol inhibited infection by 64%-67% (IC50 values 140-160 nmol/L). Fulvestrant reverted the inhibition by 17ß-estradiol in a dose-dependent manner. 17ß-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: 17ß-estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.

Early activation of interferon-stimulated genes in human liver allografts: relationship with acute rejection and histological outcome.

BACKGROUND: Innate immunity mechanisms have been shown to play a paramount role in organ transplantation. Our aim was to investigate the hypothesis that activation of the interferon system may affect clinically relevant outcomes, such as acute rejection and/or early fibrosis progression, after liver transplantation. METHODS: We studied 71 consecutive recipients (57 males; 25 with hepatitis C) who underwent two per protocol graft biopsies: the first, within 60 days after the transplant operation (median 24) and the second, after 1 year. The mRNA expression for five interferon-stimulated genes (Mx1, OAS2, PKR, IRF7A, IFI16) was measured on the first biopsy specimens. The main outcome measures were acute rejection during the first post-transplant year and fibrosis progression at the second biopsy. RESULTS: On multivariate analysis, the independent predictors of gene expression were hepatitis C (Mx1, OAS2, PKR and IFI16), donor age (IFI16) and recipient gender (IRF7A) (P < .05 for all). During the first post-transplant year, 19/71 patients (27%) had acute cellular rejection. At multivariate analysis, acute cellular rejection was independently predicted by high IRF7A mRNA expression. At the end of follow-up, 25 patients had some degree of fibrosis (F2 or higher in seven cases). On multivariate analysis, hepatitis C etiology, recipient age, and OAS2 overexpression were independent predictors of early fibrosis progression. CONCLUSIONS: In the early postoperative period of liver transplantation, interferon-stimulated gene activation is dependent on hepatitis C recurrence (the main factor responsible for early fibrosis progression) and donor age, and is related to the risk of acute cellular rejection.