Ficolin-2 inhibits hepatitis C virus infection, whereas apolipoprotein E3 mediates viral immune escape

• Published in: The Journal of immunology (1950) 2014-07, Vol.193 (2), p.783-796
• Main Authors: Zhao, Yinglan, Ren, Yushan, Zhang, Xuping, Zhao, Ping, Tao, Wanyin, Zhong, Jin, Li, Qiao, Zhang, Xiao-Lian
• Format: Article
• Language: English
• Subjects: Apolipoprotein E3 - genetics; Apolipoprotein E3 - immunology; Apolipoprotein E3 - metabolism; Binding, Competitive - immunology; Blotting, Western; Cell Line, Tumor; Ficolins; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HEK293 Cells; HeLa Cells; Hepacivirus - genetics; Hepacivirus - immunology; Hepacivirus - physiology; Hepatitis C virus; Host-Pathogen Interactions - immunology; Humans; Lectins - genetics; Lectins - immunology; Lectins - metabolism; Mannans - immunology; Mannans - metabolism; Microscopy, Confocal; Polysaccharides - immunology; Polysaccharides - metabolism; Protein Binding - immunology; Receptors, LDL - genetics; Receptors, LDL - immunology; Receptors, LDL - metabolism; RNA Interference; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - immunology; Scavenger Receptors, Class B - metabolism; Tetraspanin 28 - genetics; Tetraspanin 28 - immunology; Tetraspanin 28 - metabolism; Tumor Escape - genetics; Tumor Escape - immunology; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; Viral Envelope Proteins - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302563

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.