Understanding human neutralizing antibodies to hepatitis C virus

描述(由申请人提供)：国立卫生研究院肝病行动计划中强调的研究目标之一是开发包括抗病毒抗体在内的方法，以防止丙型肝炎病毒(丙型肝炎病毒)在肝移植后复发。丙型肝炎病毒 相关的肝功能衰竭是肝移植最常见的适应症，但丙型肝炎病毒的复发总是发生在移植后，并可导致移植物的迅速丢失。免疫抑制的肝移植受者对干扰素和利巴韦林的副作用耐受性差，因此迫切需要在移植环境中预防和/或治疗丙型肝炎病毒的新策略。这项应用的长期目标是开发一种有效的、可耐受的抗体鸡尾酒，以防止丙型肝炎复发，同样的治疗方法也可能在医疗保健/实验室工作人员意外接触病毒的情况下或在高危人群中预防感染。其具体目的是：(1)通过噬菌体展示抗体技术制备针对不同保守的丙型肝炎病毒中和病毒表位的人源性单抗；(2)通过功能筛选产生高效的丙型肝炎病毒中和抗体；(3)了解抗体中和病毒的机制；(4)评价单抗在保护新近发展的基因人源化小鼠模型中的有效性，以用于研究多种异源丙型肝炎病毒的挑战。证明抗体或抗体鸡尾酒具有显著的保护作用，将为进一步研究被动抗体方法在临床上预防丙型肝炎复发提供科学基础。

DESCRIPTION (provided by applicant): One of the research goals highlighted in the Action Plan for Liver Disease of the National Institutes of Health is to develop means, including anti-viral antibodies, to prevent recurrence of hepatitis C virus (HCV) after liver transplantation. HCV associated liver failure is the most common indication for liver transplantation but recurren HCV invariably occurs after transplantation and can lead to rapid graft loss. The immunosuppressed liver transplant recipients tolerate the side effects of IFN-¿ and ribavirin poorly and therefore new strategies for prevention and/or treatment of HCV in the transplant setting are urgently required. The long-term objective of this application is to develop an effective and tolerable antibody cocktail to prevent recurrent HCV, and the same treatment may also be useful in preventing infection in the cases of accidental virus exposure of healthcare/laboratory workers, or in high risk populations. The specific aims are (i) to generate human monoclonal antibodies (mAbs) to diverse conserved neutralizing viral epitopes of HCV by phage-display antibody technology; (ii) to generate highly potent HCV neutralizing antibodies by function screen; (iii) to understand the mechanisms of virus neutralization by the antibodies; (iv) to evaluate the efficacy of the mAbs in protecting a recently developed genetically humanized mouse model for HCV study upon challenges by multiple heterologous HCV genotypes. A demonstration of significant protection by the antibody or antibody cocktail would provide the scientific foundation for further investigation of this passive antibody approach in th prevention of recurrent HCV in clinical settings.