Vercauteren Koen, Van Den Eede Naomi, Mesalam Ahmed Atef, Belouzard Sandrine, Catanese Maria Teresa, Bankwitz Dorothea, Wong-Staal Flossie, Cortese Riccardo, Dubuisson Jean, Rice Charles M, Pietschmann Thomas, Leroux-Roels Geert, Nicosia Alfredo, Meuleman Philip
Department of Clinical Chemistry, Microbiology and Immunology, CEVAC, Gent, Belgium.
Hepatology. 2014 Nov;60(5):1508-18. doi: 10.1002/hep.27196. Epub 2014 Jul 30.
Hepatitis C virus (HCV)-induced endstage liver disease is currently a major indication for liver transplantation. After transplantation the donor liver inevitably becomes infected with the circulating virus. Monoclonal antibodies (mAbs) against the HCV coreceptor scavenger receptor class B type I (SR-BI) inhibit HCV infection of different genotypes, both in cell culture and in humanized mice. Anti-SR-BI mAb therapy is successful even when initiated several days after HCV exposure, supporting its potential applicability to prevent HCV reinfection of liver allografts. However, HCV variants with reduced SR-BI dependency have been described in the literature, which could potentially limit the use of SR-BI targeting therapy. In this study we show, both in a preventative and postexposure setting, that humanized mice infected with HCV variants exhibiting increased in vitro resistance to SR-BI-targeting molecules remain responsive to anti-SR-BI mAb therapy in vivo. A 2-week antibody therapy readily cleared HCV RNA from the circulation of infected humanized mice. We found no evidence supporting increased SR-BI-receptor dependency of viral particles isolated from humanized mice compared to cell culture-produced virus. However, we observed that, unlike wild-type virus, the in vitro infectivity of the resistant variants was inhibited by both human high density lipoprotein (HDL) and very low density lipoprotein (VLDL). The combination of mAb1671 with these lipoproteins further increased the antiviral effect.
HCV variants that are less dependent on SR-BI in vitro can still be efficiently blocked by an anti-SR-BI mAb in humanized mice. Since these variants are also more susceptible to neutralization by anti-HCV envelope antibodies, their chance of emerging during anti-SR-BI therapy is severely reduced. Our data indicate that anti-SR-BI receptor therapy could be an effective way to prevent HCV infection in a liver transplant setting.
丙型肝炎病毒（HCV）引起的终末期肝病目前是肝移植的主要指征。移植后，供体肝脏不可避免地会被循环病毒感染。针对HCV共受体B类I型清道夫受体（SR-BI）的单克隆抗体（mAb）在细胞培养和人源化小鼠中均能抑制不同基因型的HCV感染。即使在HCV暴露数天后开始使用抗SR-BI mAb治疗也取得了成功，这支持了其在预防肝移植受者HCV再感染方面的潜在适用性。然而，文献中已描述了对SR-BI依赖性降低的HCV变体，这可能会限制靶向SR-BI治疗的应用。在本研究中，我们发现在预防和暴露后情况下，感染了对靶向SR-BI分子体外耐药性增加的HCV变体的人源化小鼠，在体内对抗SR-BI mAb治疗仍有反应。为期2周的抗体治疗能迅速清除感染的人源化小鼠循环中的HCV RNA。我们没有发现证据支持与细胞培养产生的病毒相比，从人源化小鼠分离的病毒颗粒对SR-BI受体的依赖性增加。然而，我们观察到，与野生型病毒不同，耐药变体的体外感染性受到人高密度脂蛋白（HDL）和极低密度脂蛋白（VLDL）的抑制。mAb1671与这些脂蛋白联合使用进一步增强了抗病毒效果。
在体外对SR-BI依赖性较低的HCV变体在人源化小鼠中仍能被抗SR-BI mAb有效阻断。由于这些变体也更容易被抗HCV包膜抗体中和，它们在抗SR-BI治疗期间出现的可能性会大大降低。我们的数据表明，抗SR-BI受体治疗可能是预防肝移植环境中HCV感染的有效方法。
