Gilead Sciences, Inc., Foster City, California, United States of America.
PLoS One. 2022 Aug 4;17(8):e0270273. doi: 10.1371/journal.pone.0270273. eCollection 2022.
Chronic hepatitis B virus (HBV) infection is characterized by the presence of high circulating levels of non-infectious lipoprotein-like HBV surface antigen (HBsAg) particles thought to contribute to chronic immune dysfunction in patients. Lipid and metabolomic analysis of humanized livers from immunodeficient chimeric mice (uPA/SCID) revealed that HBV infection dysregulates several lipid metabolic pathways. Small molecule inhibitors of lipid biosynthetic pathway enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase, and subtilisin kexin isozyme-1/site-1 protease in HBV-infected HepG2-NTCP cells demonstrated potent and selective reduction of extracellular HBsAg. However, a liver-targeted ACC inhibitor did not show antiviral activity in HBV-infected liver chimeric mice, despite evidence of on-target engagement. Our study suggests that while HBsAg production may be dependent on hepatic de novo lipogenesis in vitro, this may be overcome by extrahepatic sources (such as lipolysis or diet) in vivo. Thus, a combination of agents targeting more than one lipid metabolic pathway may be necessary to reduce HBsAg levels in patients with chronic HBV infection.
慢性乙型肝炎病毒（HBV）感染的特征是存在高循环水平的非传染性脂蛋白样 HBV 表面抗原（HBsAg）颗粒，这些颗粒被认为导致患者慢性免疫功能障碍。对免疫缺陷嵌合小鼠（uPA/SCID）的人源化肝脏进行脂质和代谢组学分析表明，HBV 感染会使几种脂质代谢途径失调。在 HBV 感染的 HepG2-NTCP 细胞中，几种脂质生物合成途径酶（乙酰辅酶 A 羧化酶 [ACC]、脂肪酸合酶和枯草杆菌蛋白酶 kexin 同工酶 1/位点 1 蛋白酶）的小分子抑制剂可显著选择性地降低细胞外 HBsAg。然而，尽管有靶点结合的证据，但在 HBV 感染的肝嵌合小鼠中，一种肝靶向 ACC 抑制剂并未显示出抗病毒活性。我们的研究表明，虽然 HBsAg 的产生可能依赖于体外的肝脏从头脂肪生成，但在体内可能会被肝外来源（如脂肪分解或饮食）所克服。因此，为降低慢性 HBV 感染患者的 HBsAg 水平，可能需要联合使用多种靶向不同脂质代谢途径的药物。
