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: 4.44). 10/2004; 78(17):9224-32. DOI: 10.1128/JVI.78.17.9224-9232.2004
Source: PubMed


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.

Download full-text


Available from: Anne Op De Beeck, Feb 26, 2014
  • Source
    • "The second major specificity of NAb is directed toward sequences involved in CD81 binding. Antibodies specific to the CD81 binding site located on the surface of E2 are frequently cross neutralizing due to the high degree of sequence conservation (Keck et al., 2004a; Johansson et al., 2007; Law et al., 2008). Residues involved in binding CD81 have been mapped by performing mutagenesis of E2 RBD E1/E2 and E1/E2 incorporated into HCVpp and is summarized in Table 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV) infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. HCV encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs) to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor class B type 1. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of NAbs to prevent HCV infection, the targets of the NAb response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.
    Full-text · Article · Jul 2014 · Frontiers in Microbiology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2014 · International Journal of Pharmacy and Biological Sciences
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jul 2013 · Clinical and Developmental Immunology
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.