Hepatitis C virus E2 has three immunogenic domains containing conformational epitopes with distinct properties and biological functions

Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Journal of Virology (Impact Factor: 4.65). 10/2004; 78(17):9224-32. DOI: 10.1128/JVI.78.17.9224-9232.2004
Source: PubMed

ABSTRACT Mechanisms of virion attachment, interaction with its receptor, and cell entry are poorly understood for hepatitis C virus (HCV) because of a lack of an efficient and reliable in vitro system for virus propagation. Infectious HCV retroviral pseudotype particles (HCVpp) were recently shown to express native E1E2 glycoproteins, as defined in part by HCV human monoclonal antibodies (HMAbs) to conformational epitopes on E2, and some of these antibodies block HCVpp infection (A. Op De Beeck, C. Voisset, B. Bartosch, Y. Ciczora, L. Cocquerel, Z. Y. Keck, S. Foung, F. L. Cosset, and J. Dubuisson, J. Virol. 78:2994-3002, 2004). Why some HMAbs are neutralizing and others are nonneutralizing is looked at in this report by a series of studies to determine the expression of their epitopes on E2 associated with HCVpp and the role of antibody binding affinity. Antibody cross-competition defined three E2 immunogenic domains with neutralizing HMAbs restricted to two domains that were also able to block E2 interaction with CD81, a putative receptor for HCV. HCVpp immunoprecipitation showed that neutralizing and nonneutralizing domains are expressed on E2 associated with HCVpp, and affinity studies found moderate-to-high-affinity antibodies in all domains. These findings support the perspective that HCV-specific epitopes are responsible for functional steps in virus infection, with specific antibodies blocking distinct steps of virus attachment and entry, rather than the perspective that virus neutralization correlates with increased antibody binding to any virion surface site, independent of the epitope recognized by the antibody. Segregation of virus neutralization and sensitivity to low pH to specific regions supports a model of HCV E2 immunogenic domains similar to the antigenic structural and functional domains of other flavivirus envelope E glycoproteins.

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Available from: Anne Op De Beeck, Feb 26, 2014
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    • "Interaction of E2 with CD81 on B or T cells has been reported to result in B-cell aggregation and a lowering of the threshold for T-and B-cell activation [12] [13] [14]. The N-terminal 27 residues of E2 (HVR1); aa 384–410, show a very high degree of variation, both within isolates and genotypes, and this portion of the sequence is considered as a leading contributor to disease progression due the emergence of new viral mutants or " quasispecies " induced by the host immune system [15] [16] [17]. This study was designed to amplify HCV-E2 protein encoding sequence from HCV-infected Egyptian patients and compare it to other HCV-envelope sequences from different geographical settings. "
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    ABSTRACT: In this study, RNA isolated from sera of Egyptian HCV-patients was used to amplify a fragment of a M. wt. of ~800pb corresponding to a partial sequence of the HCV-E2 encoding gene. The amplified fragment was cloned, sequenced and the nucleotide blast analysis of our sequence revealed partial homology with previously published E2-genes of viral isolates from different locations; the highest match (88%) was annotated with a Japanese isolate suggesting that our herein characterized HCV-E2 partial sequence is a novel one. The impact of HCV-E2 sequence variability will be discussed.
    International Journal of Pharmacy and Biological Sciences 02/2014; 9(1):138-143. DOI:10.9790/3008-0914138143
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    • "In addition to this major antigenic region overlapping the CD81 binding site, other antigenic domains have also been defined in independent studies by reactivity to human mAbs. A region containing a typerestricted neutralization epitope (AR2) closely overlaps the " Antigenic Domain C, " defined by the mAbs CBH-7 and AR2A, centred on an asparagine residue at position 540 [46] [72]. While this epitope region is not extensively characterized, competition assays revealed that this epitope is discrete from those recognized by murine conformation-independent mAbs. "
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    ABSTRACT: Hepatitis C virus (HCV) is the major cause of chronic liver disease as well as the major indication for liver transplantation worldwide. Current standard of care is not completely effective, not administrable in grafted patients, and burdened by several side effects. This incomplete effectiveness is mainly due to the high propensity of the virus to continually mutate under the selective pressure exerted by the host immune response as well as currently administered antiviral drugs. The E2 envelope surface glycoprotein of HCV (HCV/E2) is the main target of the host humoral immune response and for this reason one of the major variable viral proteins. However, broadly cross-neutralizing monoclonal antibodies (mAbs) directed against HCV/E2 represent a promising tool for the study of virus-host interplay as well as for the development of effective prophylactic and therapeutic approaches. In the last few years many anti-HCV/E2 mAbs have been evaluated in preclinical and clinical trials as possible candidate antivirals, particularly for administration in pre- and post-transplant settings. In this review we summarize the antigenic and structural characteristics of HCV/E2 determined through the use of anti-HCV/E2 mAbs, which, given the absence of a crystal structure of this glycoprotein, represent currently the best tool available.
    Clinical and Developmental Immunology 07/2013; 2013:450963. DOI:10.1155/2013/450963 · 2.93 Impact Factor
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    • "Broadly cross-neutralizing anti-HCV/E2 human mAbs are typically directed against functionally important residues highly conserved among different genotypes (Broering et al., 2009; Johansson et al., 2007; Keck et al., 2008, 2004; Mancini et al., 2009; Owsianka et al., 2008; Perotti et al., 2008; Sabo et al., 2011). This aspect is crucial for the possible therapeutic in vivo use of such mAbs, but it may not be sufficient since it has been recently supposed that other Ab populations may interfere with their neutralizing activity (Burioni et al., 2001; Di Lorenzo et al., 2011; Zhang et al., 2009). "
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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.
    Antiviral research 08/2012; 96(1):82-9. DOI:10.1016/j.antiviral.2012.07.013 · 3.94 Impact Factor
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