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Published on: May 10, 2022
17,β-estradiol inhibits hepatitis C virus mainly by interference with the release phase of its life cycle
Andrea Magri1,2, Matteo N Barbaglia1, Chiara Z Foglia1
1Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
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% (IC50 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.
Insights
17β-estradiol significantly inhibits hepatitis C virus (HCV) infection by targeting its intracellular receptors. This estrogen primarily interferes with the late stages of the HCV life cycle, including assembly and release.
Area of Science:
- Hepatology
- Virology
- Endocrinology
Background:
- Oestrogen and oestrogen-mediated signalling are known to protect against hepatitis C virus (HCV) infection.
- The precise mechanisms by which oestrogens exert their protective effects remain incompletely understood.
Purpose of the Study:
- To investigate which specific phases of the hepatitis C virus (HCV) life cycle are affected by oestrogens.
- To elucidate the role of 17β-estradiol in modulating HCV infection.
Main Methods:
- Huh7 cells infected with JFH1 virus (genotype 2a) were treated with various hormones, including 17β-estradiol, and its effects on viral entry, replication, and release were assessed.
- Dose-response curves were used to determine half maximal inhibitory concentration (IC50) values.
- A dual-step infection model was employed to evaluate the impact of 17β-estradiol on both primary and secondary HCV infections.
Main Results:
- 17β-estradiol demonstrated significant inhibition of HCV infection (64%-67%), with IC50 values ranging from 140-160 nmol/L.
- The inhibitory effect of 17β-estradiol was dose-dependently reversed by the receptor antagonist fulvestrant.
- 17β-estradiol had minimal impact on viral entry and replication but significantly reduced extracellular HCV RNA and infectivity, particularly in secondary infections.
Conclusions:
- 17β-estradiol inhibits hepatitis C virus (HCV) infection by acting through intracellular receptors.
- The primary mechanism of inhibition involves interference with the late stages of the HCV life cycle, specifically viral assembly and release.
- These findings highlight a potential therapeutic role for oestrogen-based therapies in managing HCV infection.
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