A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo
A Human monoclonal antibody targeting scavenger receptor class B type I precludes hepatitis C virus infection and viral spread in vitro and in vivo
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DOI：
10.1002/hep.24692
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发表时间：
2012-02-01
期刊：
影响因子：
13.5
通讯作者：
Nicosia, Alfredo
中科院分区：
文献类型：
--
作者：
Meuleman, Philip;Catanese, Maria Teresa;Nicosia, Alfredo
慢性丙型肝炎病毒（HCV）感染引起的终末期肝病是西方世界肝移植的主要指征。然而，移植的供体肝脏被循环病毒立即再感染是不可避免的，并且肝脏疾病的进展比原始疾病快得多。标准的抗病毒治疗在肝移植患者中耐受性不好，通常无效，而抗HCV免疫治疗受到病毒的极端遗传多样性及其通过细胞-细胞接触传播的能力的阻碍。我们制备了抗清道夫受体B I型（SR-BI）的人源单克隆抗体（mAb）16-71，其可以有效地预防细胞培养衍生的HCV（HCV-HCV）对Huh-7.5肝癌细胞和原代肝细胞的感染。使用Huh7.5共培养系统，我们证明了mAb 16 -71干扰HCV的直接细胞间传播。最后，我们评估了mAb 16 -71在人肝尿激酶型纤溶酶原激活物、严重联合免疫缺陷（uPA-SCID）小鼠（嵌合小鼠）中的体内功效。在病毒接种前1天开始的2周抗SR-BI治疗完全保护所有嵌合小鼠免受不同基因型的血清来源的HCV感染。此外，在病毒接种后3天开始的9天暴露后治疗（当动物中已经观察到病毒血症时）抑制了未处理对照动物中观察到的快速病毒传播。停止抗SR-BI特异性抗体治疗后，观察到病毒载量升高。结论：使用体外细胞培养和人肝嵌合小鼠模型，我们表明，针对HCV辅助受体SR-BI的人单克隆抗体完全防止多种HCV基因型的感染和肝内传播。这一策略可能是一种有效的方法，以防止感染的同种异体肝移植后慢性丙型肝炎患者，甚至可能持有的承诺，为预防病毒反弹期间或之后的抗病毒治疗。（肝脏学2012）
Endstage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation in the Western world. However, immediate reinfection of the grafted donor liver by circulating virus is inevitable and liver disease progresses much faster than the original disease. Standard antiviral therapy is not well tolerated and usually ineffective in liver transplant patients, whereas anti-HCV immunotherapy is hampered by the extreme genetic diversity of the virus and its ability to spread by way of cell-cell contacts. We generated a human monoclonal antibody against scavenger receptor class B type I (SR-BI), monoclonal antibody (mAb)16-71, which can efficiently prevent infection of Huh-7.5 hepatoma cells and primary hepatocytes by cell-culture-derived HCV (HCVcc). Using an Huh7.5 coculture system we demonstrated that mAb16-71 interferes with direct cell-to-cell transmission of HCV. Finally we evaluated the in vivo efficacy of mAb16-71 in human liver urokinase-type plasminogen activator, severe combined immune deficiency (uPA-SCID) mice (chimeric mice). A 2-week anti-SR-BI therapy that was initiated 1 day before viral inoculation completely protected all chimeric mice from infection with serum-derived HCV of different genotypes. Moreover, a 9-day postexposure therapy that was initiated 3 days after viral inoculation (when viremia was already observed in the animals) suppressed the rapid viral spread observed in untreated control animals. After cessation of anti-SR-BI-specific antibody therapy, a rise of the viral load was observed. Conclusion: Using in vitro cell culture and human liver-chimeric mouse models, we show that a human mAb targeting the HCV coreceptor SR-BI completely prevents infection and intrahepatic spread of multiple HCV genotypes. This strategy may be an efficacious way to prevent infection of allografts following liver transplantation in chronic HCV patients, and may even hold promise for the prevention of virus rebound during or following antiviral therapy. (HEPATOLOGY 2012)