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.

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 and to understand the molecular mechanisms of their neutralizing activities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079031-06
Application #
8663827
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Koshy, Rajen
Project Start
2008-09-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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