Broadly neutralizing antibodies abrogate established hepatitis C virus infection

Creators: 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

Abstract

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.

Additional Information

© 2014 American Association for the Advancement of Science. Received for publication 12 May 2014. Accepted for publication 28 August 2014. We thank J. Sable, E. Castillo, B. Flatley, S. Shirley, and A. Webson for excellent laboratory support. S. Mazel and the Rockefeller University Flow Cytometry Core Facility, and R. Tolwani and the staff of the Comparative Bioscience Center provided outstanding technical support. M. Grompe (OHSU) provided the FAH−/− founder mice. Funding: This study was supported in part by grants from National Institute of Diabetes and Digestive and Kidney Diseases; K08DK090576 (to Y.P.d.J.), R01AI072613 and R01AI099284 (to C.M.R.), R01 AI10730101 (to A.P.), R01AI079031 (to M.L.), and R01AI071084 (to D.R.B.) from the National Institute for Allergy and Infectious Disease; R01CA057973 (to C.M.R.) from the National Cancer Institute; The Bill and Melinda Gates Foundation; The Starr Foundation; the Greenberg Medical Research Institute; the Richard Salomon Family Foundation; the Ronald A. Shellow, M.D. Memorial Fund; the MGM Mirage Voice Foundation; Gregory F. Lloyd Memorial contributions; and anonymous donors. The Immunohistochemistry Core Laboratory at New York University (NYU) Medical Center is funded in part by the NYU Cancer Institute. The NYU Cancer Center is supported in part by grant 5P30CA016087-32 from the National Cancer Institute. M.D. was supported by postdoctoral fellowship from the German Research Foundation (Deutsche Forschungsgesellschaft). Y.P.d.J. was a recipient of an American Gastroenterological Association Research Scholar Award. A.P. is a recipient of a Liver Scholar Award from the American Liver Foundation. The funding sources were not involved in the study design, collection, analysis, and interpretation of data or in the writing of the report.

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Supplemental Material - 6-254ra129_SM.pdf

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