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

Division of Hematology and Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2009; 106(18):7537-41. DOI: 10.1073/pnas.0902749106
Source: PubMed


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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Available from: Hisayoshi Watanabe
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    • "Finally, the immune system itself may incidentally enable HCV persistence by the presence of antibodies capable to interfere and block activity of nAbs [85] [86]. Despite these challenges, broadly cross-neutralizing monoclonal antibodies, directed against the E2 envelope glycoprotein that can efficiently block HCV infection of various genotypes, have been isolated from HCV-chronically infected patients or immunized animals [87] [88] [89]. "
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    ABSTRACT: Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus–host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.
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    • "A subset of epitope II directed non-neutralizing antibodies have been reported to interfere with the capacity of epitope I antibodies to neutralize virus (Zhang et al., 2009) while other epitope II-directed NAbs act cooperatively with epitope I specific NAbs (Keck et al., 2012, 2013). The ability of neutralizing antibodies directed toward epitope II to prevent neutralization escape suggests that they are a highly desirable component of the antibody response to any HCV vaccine but it is not clear what proportions of antibodies specific to epitope II have neutralizing/non-neutralizing activity in natural infection or in vaccination. "
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    • "In the case of HCV, broadly crossneutralizing Abs (bnAbs) are most effective when directed against highly conserved and functionally critical epitopes (e.g., the CD81-binding site) among different genotypes [17–27]. However the binding of these HCV bnAbs may be inhibited by the presence of non-nAbs that bind proximal to the critical residues [28–34]. This hypothesis is still controversial [26] but recent experiments support the existence of interfering Ab populations [35]. "
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