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.
Highlights
In contrast with the authentic revolution we are facing in the field of antiviral therapy of hepatitis C, several long-s tanding issues concerning the natural history of Hepatitis C Virus (HCV) infection remain incompletely understood
We show that 17,β-estradiol is able to inhibit HCV life cycle in vitro, whereas no effects were observed from exposure to dehydroepiandros terone-sulphate (DHEA-S), testosterone or progesterone. 17,β-estradiol acts through its intracellular receptor signalling pathway, triggering an antiviral state able to interfere with HCV assembly and/or release and partially with viral entry, but not on viral RNA replication
With regard to the anti-HCV effects exerted by 17,β-estradiol, our data are in agreement with what has already been reported by Hayashida et al.,[25] inasmuch as we both show that exposure to oestrogen inhibits the production of infectious HCV particles in vitro
Summary
In contrast with the authentic revolution we are facing in the field of antiviral therapy of hepatitis C, several long-s tanding issues concerning the natural history of HCV infection remain incompletely understood. It has always been puzzling why gender affects so deeply the course of hepatitis C It has been consistently shown along the years that the ability to spontaneously clear HCV infection is greater in women than in men.[1,2,3,4,5] during early chronic infection (1-year post- infection), HCV RNA levels are higher in men than in women,[6] while cirrhotic progression rarely occurs in pre-menopausal women.[7] Based on these observations, it has been proposed that oestrogen and oestrogen-mediated signalling may play a role as protective factors, reducing the disease progression or increasing the chance of clearing the virus.[8] The mechanisms by which this protection occurs are unknown; the prevailing hypothesis advocates that sex hormones bind to specific receptors expressed in immune cells, thereby influencing adaptive and, most importantly, innate immune responses.[9, 10] oestrogens are not key players in the major mechanism of innate antiviral response, the JAK/STAT pathway,[11] and in other settings, the major impact of sex steroids is on the target tissue, not on immune modulation.[12] it is not inconceivable that oestrogens may determine a suboptimal environment for viral replication by completely different mechanisms. With the present in vitro study, we aimed to better define the antiviral properties of sex hormones on HCV infection, and in particular to ascertain which phase(s) of HCV life cycle is/are affected by oestrogens
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Liver international : official journal of the International Association for the Study of the Liver
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
