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 recurrent HCV invariably occurs after transplantation and can lead to rapid graft loss. The immunosuppressed liver transplant recipients tolerate the side effects of IFN-a 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 a large panel of human monoclonal antibodies (MAbs) and to identify neutralizing MAbs targeting relatively conserved neutralizing viral epitopes;(ii) to engineer the MAbs to maximize their antiviral activity and to investigate the benefits of MAb combinations over single MAbs in neutralizing diverse HCV isolates;and (iii) to demonstrate the efficacy of the best MAb combination in protecting a small chimeric animal model bearing primary human hepatocytes against challenges by multiple heterologous HCV. A demonstration of significant protection by the antibody cocktail would provide the scientific foundation for further investigation of this passive antibody approach in the prevention of recurrent HCV in clinical settings. Public Health Relevance: Hepatitis C virus (HCV)-associated liver failure is the most common indication for liver transplantation. An effective and tolerable means to prevent re-infection after liver transplant for HCV is urgently needed. The goal of this proposal is to discover a cocktail of highly potent human monoclonal antibodies to prevent recurrent HCV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079031-04
Application #
8133022
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2008-09-15
Project End
2013-05-31
Budget Start
2011-09-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$464,322
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Winer, Benjamin Y; Huang, Tiffany; Low, Benjamin E et al. (2017) Recapitulation of treatment response patterns in a novel humanized mouse model for chronic hepatitis B virus infection. Virology 502:63-72
Li, Dapeng; Wang, Xuesong; von Schaewen, Markus et al. (2017) Immunization With a Subunit Hepatitis C Virus Vaccine Elicits Pan-Genotypic Neutralizing Antibodies and Intrahepatic T-Cell Responses in Nonhuman Primates. J Infect Dis 215:1824-1831
Ding, Qiang; von Schaewen, Markus; Hrebikova, Gabriela et al. (2017) Mice Expressing Minimally Humanized CD81 and Occludin Genes Support Hepatitis C Virus Uptake In Vivo. J Virol 91:
Velázquez-Moctezuma, Rodrigo; Law, Mansun; Bukh, Jens et al. (2017) Applying antibody-sensitive hypervariable region 1-deleted hepatitis C virus to the study of escape pathways of neutralizing human monoclonal antibody AR5A. PLoS Pathog 13:e1006214
McBride, Ryan; Head, Steven R; Ordoukhanian, Phillip et al. (2016) Low-Cost Peptide Microarrays for Mapping Continuous Antibody Epitopes. Methods Mol Biol 1352:67-83
von Schaewen, Markus; Dorner, Marcus; Hueging, Kathrin et al. (2016) Expanding the Host Range of Hepatitis C Virus through Viral Adaptation. MBio 7:
Winer, Benjamin Y; Ding, Qiang; Gaska, Jenna M et al. (2016) In vivo models of hepatitis B and C virus infection. FEBS Lett 590:1987-99
Prentoe, Jannick; Velázquez-Moctezuma, Rodrigo; Foung, Steven K H et al. (2016) Hypervariable region 1 shielding of hepatitis C virus is a main contributor to genotypic differences in neutralization sensitivity. Hepatology 64:1881-1892
Li, Dapeng; von Schaewen, Markus; Wang, Xuesong et al. (2016) Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice. J Virol 90:10486-10498
Shirvani-Dastgerdi, Elham; Schwartz, Robert E; Ploss, Alexander (2016) Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. Curr Opin Virol 20:1-10

Showing the most recent 10 out of 42 publications