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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity
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Depletion of interfering antibodies in chronic hepatitis C patients and vaccinated chimpanzees reveals broad cross-genotype neutralizing activity

机译:慢性丙型肝炎患者和接种黑猩猩中干扰抗体的消耗揭示了广泛的跨基因型中和活性

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摘要

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.
机译:最近,我们使用抗丙型肝炎病毒(HCV)阳性血浆制成的人类免疫球蛋白,在E2蛋白中的412-426(表位Ⅰ)和434-446(表位Ⅱ)残基上鉴定了两个抗体表位。表位Ⅰ在基因型之间是高度保守的,而表位Ⅱ是变化的。我们发现表位Ⅰ与HCV中和有关,而非中和抗体与表位Ⅱ的结合破坏了由表位Ⅰ抗体结合介导的病毒中和。这些发现表明,如果这种干扰机制在HCV感染期间在体内起作用,则针对表位Ⅰ的中和抗体可以被干扰抗体所抑制,即使存在大量中和抗体,这也可以解释HCV的持久性。我们通过亲和力耗尽和慢性HCV感染患者和重组E1E2接种黑猩猩的血浆中表位Ⅱ特异性抗体的肽封闭来检验这一假设。我们证明,通过消除对表位Ⅱ的干扰抗体所施加的限制,可以在以前无法中和细胞培养物中的病毒原浆的血浆中揭示中和活性。此外,可以从单特异性血浆产生跨基因型中和。我们的研究有助于理解抗体介导的中和和干扰机制,并为开发更有效和更广泛反应的丙型肝炎免疫球蛋白提供了一种实用的方法。

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    Divisions of Hematology, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Hematology, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Hematology, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Viral Products and Center for Biologies Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Viral Products and Center for Biologies Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Viral Products and Center for Biologies Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Hematology, United States Food and Drug Administration, Bethesda, MD 20892;

    Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892;

    Divisions of Viral Products and Center for Biologies Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892;

    Divisions of Viral Products and Center for Biologies Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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