Zhao Yinglan, Ren Yushan, Zhang Xuping, Zhao Ping, Tao Wanyin, Zhong Jin, Li Qiao, Zhang Xiao-Lian
State Key Laboratory of Virology, Department of Immunology, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University School of Medicine, Wuhan 430071, China;
Department of Microbiology, Second Military Medical University, Shanghai 200433, China;
J Immunol. 2014 Jul 15;193(2):783-96. doi: 10.4049/jimmunol.1302563. Epub 2014 Jun 13.
Human ficolin-2 (L-ficolin/p35) is a lectin-complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during chronic hepatitis C virus (HCV) infection. In this study, we found that ficolin-2 inhibits the entry of HCV at an early stage of viral infection, regardless of the viral genotype. Ficolin-2 neutralized and inhibited the initial attachment and infection of HCV by binding to the HCV envelope surface glycoproteins E1 and E2, blocking HCV attachment to low-density lipoprotein receptor (LDLR) and scavenger receptor B1, and weakly interfering with CD81 receptor attachment. However, no interference with claudin-1 and occludin receptor attachment was observed. The C-terminal fibrinogen domain (201-313 aa) of ficolin-2 was identified as the critical binding region for the HCV-E1-E2 N-glycans, playing a critical role in the anti-HCV activity. More importantly, we found that apolipoprotein E (ApoE)3, which is enriched in the low-density fractions of HCV RNA-containing particles, promotes HCV infection and inhibits ficolin-2-mediated antiviral activity. ApoE3, but not ApoE2 and ApoE4, blocked the interaction between ficolin-2 and HCV-E2. Our data suggest that the HCV entry inhibitor ficolin-2 is a novel and promising antiviral innate immune molecule, whereas ApoE3 blocks the effect of ficolin-2 and mediates an immune escape mechanism during chronic HCV infection. HCV may be neutralized using compounds directed against the lipoprotein moiety of the viral particle, and ApoE3 may be a new target to combat HCV infection.
人纤维胶凝蛋白-2（L-纤维胶凝蛋白/p35）是一种凝集素-补体途径激活剂，存在于正常人血浆中，与传染病相关；然而，关于纤维胶凝蛋白-2在慢性丙型肝炎病毒（HCV）感染中的作用和机制知之甚少。在本研究中，我们发现纤维胶凝蛋白-2在病毒感染早期抑制HCV的进入，而与病毒基因型无关。纤维胶凝蛋白-2通过与HCV包膜表面糖蛋白E1和E2结合，中和并抑制HCV的初始附着和感染，阻断HCV与低密度脂蛋白受体（LDLR）和清道夫受体B1的附着，并微弱干扰CD81受体的附着。然而，未观察到对紧密连接蛋白-1和闭合蛋白受体附着的干扰。纤维胶凝蛋白-2的C末端纤维蛋白原结构域（201-313氨基酸）被确定为与HCV-E1-E2 N-聚糖的关键结合区域，在抗HCV活性中起关键作用。更重要的是，我们发现富含含HCV RNA颗粒低密度组分的载脂蛋白E（ApoE）3促进HCV感染并抑制纤维胶凝蛋白-介导的抗病毒活性。ApoE3而非ApoE2和ApoE4阻断纤维胶凝蛋白-2与HCV-E2之间的相互作用。我们的数据表明，HCV进入抑制剂纤维胶凝蛋白-2是一种新型且有前景的抗病毒天然免疫分子，而ApoE3在慢性HCV感染期间阻断纤维胶凝蛋白-2的作用并介导免疫逃逸机制。可以使用针对病毒颗粒脂蛋白部分的化合物中和HCV，并且ApoE3可能是对抗HCV感染的新靶点。
