Griffithsin Has Antiviral Activity against Hepatitis C Virus
Griffithsin Has Antiviral Activity against Hepatitis C Virus
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DOI：
10.1128/aac.00633-11
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发表时间：
2011-11-01
影响因子：
4.9
通讯作者：
Dubuisson, Jean
中科院分区：
文献类型：
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作者：
Meuleman, Philip;Albecka, Anna;Dubuisson, Jean
接受肝移植的丙型肝炎病毒（HCV）感染患者普遍会经历新移植肝的快速再感染。目前的治疗方案不能防止移植物再感染，此外，还观察到疾病进展加速。在本研究中，我们评估了一种使用凝集素、格里菲辛 (GRFT) 预防 HCV 感染的新策略，该策略特异性结合病毒包膜上存在的 N-连接高甘露糖寡糖。使用 HCV 伪颗粒 (HCVpp) 和 HCV 细胞培养 (HCVcc) 系统体外评估 GRFT 的抗病毒效果。我们在此表明，用 GRFT 预孵育 HCVpp 和 HCVcc 可防止 Huh-7 肝癌细胞的感染。此外，GRFT 干扰 HCV 的直接细胞间传播。 GRFT 在病毒生命周期的早期阶段发挥作用，以与基因型无关的方式干扰病毒包膜蛋白和病毒受体 CD81 之间的相互作用。使用肝脏中含有人类原代肝细胞的 uPA(+/+)-SCID 小鼠（uPA 代表尿激酶型纤溶酶原激活剂）（嵌合小鼠）评估 GRFT 预防体内感染的能力。在这个概念验证试验中，我们证明了 GRFT 可以减轻嵌合小鼠的 HCV 感染。确实被感染的接受治疗的动物表现出病毒感染动力学的相当大的延迟。我们的数据表明，GRFT 可以在体外预防 HCV 感染，并在体内减轻 HCV 感染。对接受肝移植的慢性感染 HCV 患者进行 GRFT 治疗可能是预防同种异体肝移植感染的合适策略。
Hepatitis C virus (HCV)-infected patients undergoing liver transplantation universally experience rapid reinfection of their new liver graft. Current treatment protocols do not prevent graft reinfection and, in addition, an accelerated disease progression is observed. In the present study, we have evaluated a novel strategy to prevent HCV infection using a lectin, griffithsin (GRFT) that specifically binds N-linked high-mannose oligosaccharides that are present on the viral envelope. The antiviral effect of GRFT was evaluated in vitro using the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems. We show here that preincubation of HCVpp and HCVcc with GRFT prevents infection of Huh-7 hepatoma cells. Furthermore, GRFT interferes with direct cell-to-cell transmission of HCV. GRFT acts at an early phase of the viral life cycle by interfering in a genotype-independent fashion with the interaction between the viral envelope proteins and the viral receptor CD81. The capacity of GRFT to prevent infection in vivo was evaluated using uPA(+/+)-SCID mice (uPA stands for urokinase-type plasminogen activator) that harbor human primary hepatocytes in their liver (chimeric mice). In this proof-of-concept trial, we demonstrated that GRFT can mitigate HCV infection of chimeric mice. Treated animals that did become infected demonstrated a considerable delay in the kinetics of the viral infection. Our data demonstrate that GRFT can prevent HCV infection in vitro and mitigate HCV infection in vivo. GRFT treatment of chronically infected HCV patients undergoing liver transplantation may be a suitable strategy to prevent infection of the liver allograft.