Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice
Novel human SR-BI antibodies prevent infection and dissemination of HCV in vitro and in humanized mice
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DOI：
10.1016/j.jhep.2012.02.018
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发表时间：
2012-07-01
影响因子：
25.7
通讯作者：
Nicosia, Alfredo
中科院分区：
文献类型：
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作者：
Lacek, Krzysztof;Vercauteren, Koen;Nicosia, Alfredo
背景与目的：丙型肝炎病毒（HCV）引起的终末期肝病是目前西方国家肝移植的主要适应症。移植后，供体肝脏几乎不可避免地受到循环病毒的感染，免疫抑制移植患者的疾病进展加快。目前基于聚乙二醇化干扰素和利巴韦林的标准疗法会引起严重的副作用，并且在这一人群中通常无效。因此，迫切需要新的策略来预防移植物再感染。我们之前已经证明，针对HCV共受体清道夫受体B类I型（SR-BI/Cla1）的单克隆抗体（mab）在细胞培养中抑制不同HCV基因型的感染。方法：利用噬菌体展示文库，我们生成了大量针对SR-BI的新型人单抗，并在体外和体内用人源化肝脏的uPA-SCID小鼠评估了它们在预防HCV感染和直接细胞间传播方面的有效性。结果：生成了11个特异性识别SR-BI的人单克隆抗体。两种抗体mAb8和mAb151在体外显示出最高的结合和抑制特性，并且也干扰细胞间的直接传播。对人源化小鼠的研究表明，这两种抗体都能够预防HCV感染，并且在感染后3天给药时可以阻断肝内传播和病毒扩增。有趣的是，抗sr - bi治疗对肝移植患者逃避适应性免疫反应控制的HCV变异有效。结论：本研究产生的抗sr - bi单克隆抗体可能是预防同种异体肝移植HCV再感染的新治疗工具。(C) 2012年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Hepatitis C virus ( HCV)-induced end-stage liver disease is currently the major indication for liver transplantation in the Western world. After transplantation, the donor liver almost inevitably becomes infected by the circulating virus and disease progression is accelerated in immune suppressed transplant patients. The current standard therapy, based on pegylated interferon and ribavirin, induces severe side effects and is often ineffective in this population. Therefore, new strategies to prevent graft re-infection are urgently needed. We have previously shown that monoclonal antibodies (mAbs) against the HCV co-receptor scavenger receptor class B type I (SR-BI/Cla1) inhibit infection by different HCV genotypes in cell culture.Methods: Using phage display libraries, we have generated a large set of novel human mAbs against SR-BI and evaluated their effectiveness in preventing HCV infection and direct cell-to-cell spread in vitro and in vivo using uPA-SCID mice with a humanized liver.Results: Eleven human monoclonal antibodies were generated that specifically recognize SR-BI. Two antibodies, mAb8 and mAb151, displayed the highest binding and inhibitory properties and also interfered with direct cell-to-cell spread in vitro. Studies in humanized mice showed that both antibodies were capable of preventing HCV infection and could block intrahepatic spread and virus amplification when administered 3 days after infection. Interestingly, anti-SR-BI therapy was effective against an HCV variant that escaped the control of the adaptive immune response in a liver transplant patient.Conclusions: The anti-SR-BI mAbs generated in this study may represent novel therapeutic tools to prevent HCV re-infection of liver allografts. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.