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.
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.
|von Schaewen, Markus; Dorner, Marcus; Hueging, Kathrin et al. (2016) Expanding the Host Range of Hepatitis C Virus through Viral Adaptation. MBio 7:|
|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|
|O'Shea, Daire; Law, John; Egli, Adrian et al. (2016) Prevention of hepatitis C virus infection using a broad cross-neutralizing monoclonal antibody (AR4A) and epigallocatechin gallate. Liver Transpl 22:324-32|
|Prentoe, Jannick; VelÃ¡zquez-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|
|Kong, Leopold; Lee, David E; Kadam, Rameshwar U et al. (2016) Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen. Proc Natl Acad Sci U S A :|
|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|
|Fusil, Floriane; Calattini, Sara; Amirache, Fouzia et al. (2015) A Lentiviral Vector Allowing Physiologically Regulated Membrane-anchored and Secreted Antibody Expression Depending on B-cell Maturation Status. Mol Ther 23:1734-47|
|Winer, Benjamin Y; Ploss, Alexander (2015) Determinants of hepatitis B and delta virus host tropism. Curr Opin Virol 13:109-16|
|Kong, Leopold; Jackson, Kelli N; Wilson, Ian A et al. (2015) Capitalizing on knowledge of hepatitis C virus neutralizing epitopes for rational vaccine design. Curr Opin Virol 11:148-57|
|Law, Mansun (2015) Editorial overview: Preventive and therapeutic vaccines (B cell epitope vaccine). Curr Opin Virol 11:viii-x|
Showing the most recent 10 out of 35 publications