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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: 9.81). 05/2009; 106(18):7537-41. DOI: 10.1073/pnas.0902749106
Source: PubMed

ABSTRACT 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, Jul 17, 2015
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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.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.09.009 · 10.40 Impact Factor
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    • "To better define the critical E2 residues involved, the binding of AP33, e20, e137 and e509 to a panel of alanine point-mutated H77- derived HCV/E1–E2 (1a) clones was determined. In particular, an alanine scanning mutagenesis was performed in the 436–447 region (epitope II), the interfering epitope described by Zhang et al. (2009). Moreover, we also evaluated the e509 binding features on two additional regions, 412–423 (epitope I) and 483–549, both critical for HCV/E2 binding to CD81 and already investigated for e20, e137 and AP33 (Mancini et al., 2009; Owsianka et al., 2006; Perotti et al., 2008; Tarr et al., 2006). "
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    ABSTRACT: The suggested HCV escape mechanism consisting in the elicitation of antibody (Ab) subpopulations interfering with the neutralizing activity of other Abs has recently been questioned. In particular, it was originally reported that Abs directed against the 436-447 region (epitope II) of HCV/E2 glycoprotein may interfere with the neutralizing Abs directed against the 412-423 region (epitope I) involved in the binding to CD81. In this paper, we investigate on the molecular features of this phenomenon describing an anti-HCV/E2 monoclonal Ab (mAb) (e509) endowed with a weak neutralizing activity, and whose epitope is centered on epitope II. Interestingly, e509 influenced the potent neutralizing activity of AP33, one of the best characterized anti-HCV/E2 mAb, whereas it did not show any interfering activity against two other broadly neutralizing mAbs (e20 and e137), whose epitopes partially overlap with that of e509 and which possibly displace it from the antigen. These data may give a possible clue to interpret the conflicting studies published to date on the mechanism of interference, suggesting the existence of at least two groups of broadly neutralizing anti-HCV/E2 Abs: (i) those whose epitope is focused on the 412-423 CD81-binding region and whose activity may be hampered by other Abs directed against the 436-447 region, and (ii) those directed against CD81-binding regions but whose epitope contains also residues within the 436-447 region recognized by interfering mAbs, thus competing with them for binding. The conflicting results of previous studies may therefore depend on the relative amount of each of these two populations in the polyclonal preparations used. Overall, a better comprehension of this phenomenon may be of importance in the set up of novel mAb-based anti-HCV therapeutic strategies.
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    • "Efficient antiviral CTL response is observed when it is primed in lymphoid organs, whereas within the liver, priming is more tend to induce T cell inactivation, tolerance or apoptosis (Guidotti & Chisari, 2006). A strong, multispecific and long-lasting T-cell immune response emerge to be important for control of viral infection (Dustin & Rice, 2007; Zhang et al., 2009). Persistent HCV unsuccessfully control by T effector cells is due to multiple causes, such as: HCV escape mutant generation, immunosuppressive effects exertion, Tregs induction, or effector T cell exhaustion or apoptosis (Bassett et al., 1999; Thimme et al., 2006; Thimme et al., 2001; Larrubia et al., 2011). "
    Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics, 11/2011; , ISBN: 978-953-307-760-4
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