Article

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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    • "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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    • "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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