Institut National de la Santé et de la Recherche Médicale, Unité 748, Strasbourg, France.
J Exp Med. 2010 Aug 30;207(9):2019-31. doi: 10.1084/jem.20090766. Epub 2010 Aug 16.
End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is a leading cause for liver transplantation (LT). Due to viral evasion from host immune responses and the absence of preventive antiviral strategies, reinfection of the graft is universal. The mechanisms by which the virus evades host immunity to reinfect the liver graft are unknown. In a longitudinal analysis of six HCV-infected patients undergoing LT, we demonstrate that HCV variants reinfecting the liver graft were characterized by efficient entry and poor neutralization by antibodies present in pretransplant serum compared with variants not detected after transplantation. Monoclonal antibodies directed against HCV envelope glycoproteins or a cellular entry factor efficiently cross-neutralized infection of human hepatocytes by patient-derived viral isolates that were resistant to autologous host-neutralizing responses. These findings provide significant insights into the molecular mechanisms of viral evasion during HCV reinfection and suggest that viral entry is a viable target for prevention of HCV reinfection of the liver graft.
慢性丙型肝炎病毒 (HCV) 感染导致的终末期肝病是肝移植 (LT) 的主要原因。由于病毒逃避宿主免疫反应和缺乏预防性抗病毒策略，移植物的再感染是普遍存在的。病毒逃避宿主免疫并重新感染肝移植物的机制尚不清楚。在对六名接受 LT 的 HCV 感染患者进行的纵向分析中，我们证明了与移植后未检测到的变异体相比，重新感染肝移植物的 HCV 变异体具有高效进入和对移植前血清中存在的抗体的低中和能力的特征。针对 HCV 包膜糖蛋白或细胞进入因子的单克隆抗体可有效中和患者来源的病毒分离株对人肝细胞的感染，而这些病毒分离株对自体宿主中和反应具有抗性。这些发现为 HCV 再感染过程中病毒逃逸的分子机制提供了重要的见解，并表明病毒进入是预防 HCV 肝移植物再感染的可行靶标。
