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.

译文

背景与目的:雌激素和雌激素介导的信号转导机制尚不完全清楚,可预防丙型肝炎病毒。我们旨在确定丙型肝炎病毒生命周期的哪个阶段受到雌激素的影响。
方法:将感染JFH1病毒(基因型2a)的Huh7细胞暴露于脱氢表雄酮,睾丸激素,孕酮和17β-雌二醇(经/不经其受体拮抗剂氟维司汀测试)。建立剂量反应曲线以计算最大抑制浓度的一半。为了剖析17β-雌二醇如何干扰丙型肝炎病毒生命周期的各个阶段,测量了其对丙型肝炎病毒假颗粒系统(病毒进入),亚基因组复制子N17 / JFH1和复制子细胞系Huh7-J17(病毒)的影响。复制)。最后,在两步感染模型中,从暴露于激素的感染细胞中收集的感染上清液被用于感染幼稚细胞。
结果:孕酮和睾丸激素对丙型肝炎病毒无抑制作用。脱氢表雄酮仅具有轻度抑制作用。相比之下,17β-雌二醇可将感染抑制64%-67%(IC50值为140-160nmol / L)。氟韦斯特兰以剂量依赖的方式逆转了17β-雌二醇的抑制作用。 17β-雌二醇仅对C型肝炎病毒假颗粒产生轻微抑制作用(<20%),对表达N17 / JFH1复制子的细胞(瞬时或稳定)(Huh7-J17细胞)没有影响。在双步感染模型中,主要(134nmol / L)和继发性(100nmol / L)感染(P = .02)之间出现最大抑制浓度显着降低一半(P = .02),细胞外丙型肝炎病毒RNA和感染力降低与细胞内对应物相比,程度更高。
结论:17β-雌二醇通过其细胞内受体抑制丙型肝炎病毒,主要干扰丙型肝炎病毒生命周期的后期阶段(组装/释放)。

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