de Jong Ype P, Dorner Marcus, Mommersteeg Michiel C, Xiao Jing W, Balazs Alejandro B, Robbins Justin B, Winer Benjamin Y, Gerges Sherif, Vega Kevin, Labitt Rachael N, Donovan Bridget M, Giang Erick, Krishnan Anuradha, Chiriboga Luis, Charlton Michael R, Burton Dennis R, Baltimore David, Law Mansun, Rice Charles M, Ploss Alexander
Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY 10065, USA. Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
Sci Transl Med. 2014 Sep 17;6(254):254ra129. doi: 10.1126/scitranslmed.3009512.
In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs-AR3A, AR3B, and AR4A-delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection.
在大多数暴露于丙型肝炎病毒（HCV）的个体中，会形成慢性感染；这种长期感染反过来又会促使肝硬化和肝细胞癌等肝脏疾病的发展。针对HCV的抗体在疾病进展中的作用尚不清楚。中和抗体（nAbs）在体外和动物模型中可预防HCV感染。然而，nAbs对已建立的HCV感染的影响尚不清楚。我们证明，通过腺相关病毒载体递送的三种广泛中和抗体——AR3A、AR3B和AR4A——可在人源化小鼠中提供针对病毒攻击的保护。此外，我们提供的证据表明，nAbs可在原代肝细胞培养物和人肝嵌合小鼠模型中消除正在进行的HCV感染。这些结果展示了一种治疗方法，即通过利用HCV持续感染新肝细胞以维持慢性感染这一先前未被重视的需求来干扰HCV感染。
