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Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity

Using human immune globulins made from antihepatitis C virus (HCV)-positive plasma, we recently identified two antibody epitopes in the E2 protein at residues 412–426 (epitope I) and 434–446 (epitope II). Whereas epitope I is highly conserved among genotypes, epitope II varies. We discovered that ep...

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Autores principales: Zhang, Pei, Zhong, Lilin, Struble, Evi Budo, Watanabe, Hisayoshi, Kachko, Alla, Mihalik, Kathleen, Virata, Maria Luisa, Alter, Harvey J., Feinstone, Stephen, Major, Marian
Formato: Texto
Lenguaje:English
Publicado: National Academy of Sciences 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670884/
https://www.ncbi.nlm.nih.gov/pubmed/19380744
http://dx.doi.org/10.1073/pnas.0902749106
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author Zhang, Pei
Zhong, Lilin
Struble, Evi Budo
Watanabe, Hisayoshi
Kachko, Alla
Mihalik, Kathleen
Virata, Maria Luisa
Alter, Harvey J.
Feinstone, Stephen
Major, Marian
author_facet Zhang, Pei
Zhong, Lilin
Struble, Evi Budo
Watanabe, Hisayoshi
Kachko, Alla
Mihalik, Kathleen
Virata, Maria Luisa
Alter, Harvey J.
Feinstone, Stephen
Major, Marian
author_sort Zhang, Pei
collection PubMed
description Using human immune globulins made from antihepatitis C virus (HCV)-positive plasma, we recently identified two antibody epitopes in the E2 protein at residues 412–426 (epitope I) and 434–446 (epitope II). Whereas epitope I is highly conserved among genotypes, epitope II varies. We discovered that epitope I was implicated in HCV neutralization whereas the binding of non-neutralizing antibody to epitope II disrupted virus neutralization mediated by antibody binding at epitope I. These findings suggested that, if this interfering mechanism operates in vivo during HCV infection, a neutralizing antibody against epitope I can be restrained by an interfering antibody, which may account for the persistence of HCV even in the presence of an abundance of neutralizing antibodies. We tested this hypothesis by affinity depletion and peptide-blocking of epitope-II-specific antibodies in plasma of a chronically HCV-infected patient and recombinant E1E2 vaccinated chimpanzees. We demonstrate that, by removing the restraints imposed by the interfering antibodies to epitope-II, neutralizing activity can be revealed in plasma that previously failed to neutralize viral stock in cell culture. Further, cross-genotype neutralization could be generated from monospecific plasma. Our studies contribute to understanding the mechanisms of antibody-mediated neutralization and interference and provide a practical approach to the development of more potent and broadly reactive hepatitis C immune globulins.
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spelling pubmed-26708842009-04-21 Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity Zhang, Pei Zhong, Lilin Struble, Evi Budo Watanabe, Hisayoshi Kachko, Alla Mihalik, Kathleen Virata, Maria Luisa Alter, Harvey J. Feinstone, Stephen Major, Marian Proc Natl Acad Sci U S A Biological Sciences Using human immune globulins made from antihepatitis C virus (HCV)-positive plasma, we recently identified two antibody epitopes in the E2 protein at residues 412–426 (epitope I) and 434–446 (epitope II). Whereas epitope I is highly conserved among genotypes, epitope II varies. We discovered that epitope I was implicated in HCV neutralization whereas the binding of non-neutralizing antibody to epitope II disrupted virus neutralization mediated by antibody binding at epitope I. These findings suggested that, if this interfering mechanism operates in vivo during HCV infection, a neutralizing antibody against epitope I can be restrained by an interfering antibody, which may account for the persistence of HCV even in the presence of an abundance of neutralizing antibodies. We tested this hypothesis by affinity depletion and peptide-blocking of epitope-II-specific antibodies in plasma of a chronically HCV-infected patient and recombinant E1E2 vaccinated chimpanzees. We demonstrate that, by removing the restraints imposed by the interfering antibodies to epitope-II, neutralizing activity can be revealed in plasma that previously failed to neutralize viral stock in cell culture. Further, cross-genotype neutralization could be generated from monospecific plasma. Our studies contribute to understanding the mechanisms of antibody-mediated neutralization and interference and provide a practical approach to the development of more potent and broadly reactive hepatitis C immune globulins. National Academy of Sciences 2009-05-05 /pmc/articles/PMC2670884/ /pubmed/19380744 http://dx.doi.org/10.1073/pnas.0902749106 Text en Freely available online through the PNAS open access option.
spellingShingle Biological Sciences
Zhang, Pei
Zhong, Lilin
Struble, Evi Budo
Watanabe, Hisayoshi
Kachko, Alla
Mihalik, Kathleen
Virata, Maria Luisa
Alter, Harvey J.
Feinstone, Stephen
Major, Marian
Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title_full Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title_fullStr Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title_full_unstemmed Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title_short Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
title_sort depletion of interfering antibodies in chronic hepatitis c patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670884/
https://www.ncbi.nlm.nih.gov/pubmed/19380744
http://dx.doi.org/10.1073/pnas.0902749106
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