Centre International de Recherche en Infectiologie (CIRI), Université Lyon, Université Claude Bernard Lyon 1, INSERM, Unité1111, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5308, École Normale Supérieure (ENS) de Lyon, Lyon, France.
Laboratoire de Virologie, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.
FASEB J. 2019 Feb;33(2):2472-2483. doi: 10.1096/fj.201801181R. Epub 2018 Oct 11.
Hepatitis B virus (HBV) infection and bile acid (BA) metabolism are interdependent: infection modifies the expression of the BA nuclear receptor farnesoid X receptor (FXR)-α, and modulation of FXRα activity by ligands alters HBV replication. Mechanisms of HBV control by FXRα remain to be unveiled. FXRα silencing in HBV-infected HepaRG cells decreased the viral covalently closed circular (ccc)DNA pool size and transcriptional activity. Treatment with the FXRα agonist GW4064 inhibited FXRα proviral effect on cccDNA similarly for wild-type and hepatitis B viral X protein (HBx)-deficient virus, whereas agonist-induced inhibition of pregenomic and precore RNA transcription and viral DNA secretion was HBx dependent. These data indicated that FXRα acts as a proviral factor by 2 different mechanisms, which are abolished by FXRα stimulation. Finally, infection of C3H/HeN mice by a recombinant adeno-associated virus-2/8-HBV vector induced a sustained HBV replication in young mice in contrast with the transient decline in adult mice. Four-week GW4064 treatment of infected C3H/HeN mice decreased secretion of HBV DNA and HB surface antigen in adult mice only. These results suggest that the physiologic balance of FXRα expression and activation by bile acid is a key host metabolic pathway in the regulation of HBV infection and that FXRα can be envisioned as a target for HBV treatment.-Mouzannar, K., Fusil, F., Lacombe, B., Ollivier, A., Ménard, C., Lotteau, V., Cosset, F.-L., Ramière, C., André, P. Farnesoid X receptor α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo.
乙型肝炎病毒 (HBV) 感染和胆汁酸 (BA) 代谢是相互依存的：感染改变了 BA 核受体法尼醇 X 受体 (FXR)-α 的表达，而配体对 FXRα 活性的调节改变了 HBV 的复制。FXRα 对 HBV 的控制机制仍有待揭示。HBV 感染的 HepaRG 细胞中 FXRα 的沉默降低了病毒共价闭合环状 (ccc)DNA 池的大小和转录活性。FXRα 激动剂 GW4064 的治疗同样抑制了野生型和乙型肝炎病毒 X 蛋白 (HBx) 缺失病毒的 FXRα 前病毒对 cccDNA 的作用，而激动剂诱导的前基因组和前核心 RNA 转录和病毒 DNA 分泌的抑制作用则依赖于 HBx。这些数据表明，FXRα 通过 2 种不同的机制发挥前病毒因子的作用，而这 2 种机制都被 FXRα 刺激所消除。最后，重组腺相关病毒 2/8-HBV 载体感染 C3H/HeN 小鼠在年轻小鼠中诱导持续的 HBV 复制，而在成年小鼠中则短暂下降。4 周 GW4064 治疗感染的 C3H/HeN 小鼠仅降低了成年小鼠中 HBV DNA 和 HB 表面抗原的分泌。这些结果表明，FXRα 表达和胆汁酸激活的生理平衡是调节 HBV 感染的关键宿主代谢途径，FXRα 可以被设想为 HBV 治疗的靶点。-Mouzannar，K.，Fusil，F.，Lacombe，B.，Ollivier，A.，Ménard，C.，Lotteau，V.，Cosset，F.-L.，Ramière，C.，André，P. 法尼醇 X 受体 α 是乙型肝炎病毒的前病毒宿主因子，体外和体内实验均受配体抑制。
