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

Abstract

Background & AimsOestrogen 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.MethodsHuh7 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.ResultsProgesterone 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.Conclusions17β‐estradiol inhibits hepatitis C virus acting through its intracellular receptors, mainly interfering with late phases (assembly/release) of the hepatitis C virus life cycle.

Modulation of Oxidative Stress by 17 β-Estradiol and Genistein in Human Hepatic Cell Lines In Vitro

“…Those effects would be related to both ERs and GPER. Finally, our findings would support clinical observations about the different evolution of hepatic fibrosis in postmenopausal women or men versus premenopausal women and about the delay that hormone replacement therapy with estrogen would cause cirrhosis evolution in postmenopausal women [2, 5, 45]. …”

17β‐estradiol reduces SARS‐CoV‐2 infection in vitro

“…Moreover, castrated male mice did not show an increase in death number due to SARS‐CoV infection compared to the control group, suggesting that the susceptibility to SARS‐CoV severity could be sex‐related, and estrogen may play an important role in the disease onset. Adding another perspective, it has been demonstrated that 17β‐estradiol interferes with hepatitis C life cycle (Magri et al, 2017), suggesting a direct mechanism of steroid action on virus, rather than only by modulating host intracellular homeostatic processes. Moreover, sterols have been suggested to potentially modify virus infection capacity (Rezanka et al, 2009).…”

Sex-Dependent Outcome of Hepatitis B and C Viruses Infections: Synergy of Sex Hormones and Immune Responses?

“…The worse outcome of HCV infection in men may also be explained by the direct influence of sex hormones on HCV itself. 17β-estradiol was found to inhibit production of mature HCV virions, through ERα binding ( 65 , 66 ) and to inhibit HCV entry, through down-regulation of occludin (one of the receptors used by HCV to access the hepatocytes), in infected cell cultures ( 67 ).…”