Definition of a Conserved Immunodominant Domain on Hepatitis C Virus E2 Glycoprotein by Neutralizing Human Monoclonal Antibodies

Keck, Zhen Yong; Li, Ta Kai; Xia, Jinming; Gal-Tanamy, Meital; Olson, Oakley C.; Li, Sophia H.; Patel, Arvind H.; Ball, Jonathan K.; Lemon, Stanley M.; Foung, Steven K. H.

doi:10.1128/jvi.02475-07

Cited by 109 publications

(154 citation statements)

References 23 publications

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“…(D) Similar neutralization assays of wt and mutant viruses with a panel of human mAbs (100 g/ml). Below each mAb is the E2 domain to which it has been mapped in previous antibody competition studies (15,17). H-111 is directed against a linear epitope in E1 and was included as a control.…”

Section: Resultsmentioning

confidence: 99%

“…The murine AP33 mAb (36) and rat mAbs 3/11, 10/76b, 7/16b, 9/75b, 6/53, 11/20A, 7/59, and 9/27 have been described (26,42). Human mAbs, CBH-2, CBH-5, CBH-8C, CBH-11, CBH-4B, CBH-4D, CBH-4G, CBH-7, HC-1, HC-2, HC-11, HC-12, HC-13, and H111 were generated from peripheral blood B cells collected from HCV-infected patients, as described elsewhere (11,17). Anticore C7-50 mAb was from Affinity BioReagents (Golden, CO), and anti-CD81 JS-81 mAb from BD Pharmingen (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Although the sequence spanning residues 523-540 in E2 contributes to conformational epitopes within domain B, crosscompetition and alanine replacement studies suggest that residues 396-424, immediately downstream of HVR-1, are also involved (17,18). Importantly, immunization of mice and rats with recombinant E2 also elicits mAbs that recognize this E2 segment (20)(21)(22).…”

mentioning

confidence: 99%

“…One cluster, designated domain A, is bound by non-neutralizing antibodies, whereas two other clusters, domains B and C, bind distinctly different groups of neutralizing mAbs (16,17). Antibodies to domain B may be particularly important, as some are capable of broadly neutralizing multiple genotypes of HCV (17)(18)(19). Domain B is comprised of a cluster of discontinuous, conformation-dependent epitopes containing multiple residues involved in E2 binding to CD81, an important co-receptor for virus.…”

mentioning

confidence: 99%

“…Cross-competition analyses, coupled with alanine scanning studies of recombinant antigens, have delineated at least three immunogenic clusters of overlapping epitopes bound by functionally distinct groups of monoclonal antibodies (mAbs) isolated from infected humans (15). One cluster, designated domain A, is bound by non-neutralizing antibodies, whereas two other clusters, domains B and C, bind distinctly different groups of neutralizing mAbs (16,17). Antibodies to domain B may be particularly important, as some are capable of broadly neutralizing multiple genotypes of HCV (17)(18)(19).…”

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confidence: 99%

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In vitro selection of a neutralization-resistant hepatitis C virus escape mutant

Gal-Tanamy

Keck

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Effective immunization against hepatitis C virus (HCV) infections is likely to require the induction of both robust T and B cell immunity. Although neutralizing antibodies may play an important role in control of infection, there is little understanding of the structure of the HCV envelope glycoproteins and how they interact with such antibodies. An additional challenge for vaccine design is the genetic diversity of HCV and the rapid evolution of viral quasispecies that escape antibody-mediated neutralization. We used a cell culture-infectious, chimeric HCV with the structural proteins of genotype 1a virus to identify envelope residues contributing to the epitope recognized by a broadly neutralizing, murine monoclonal antibody, AP33. By repetitive rounds of neutralization followed by amplification, we selected a population of viral escape mutants that resist stringent neutralization with AP33 and no longer bind the antibody. Two amino acid substitutions, widely separated in the linear sequence of the E2 envelope protein (N415Y and E655G), were identified by sequencing of cloned cDNA and shown by reverse genetics analysis to contribute jointly to the AP33 resistance phenotype. The N415Y mutation substantially lowered virus fitness, most likely because of a defect in viral entry, but did not reduce binding of soluble CD81 to immobilized HCV-pseudotyped retrovirus particles. The in vitro selection of an HCV escape mutant recapitulates the ongoing evolution of antigenic variants that contributes to viral persistence in humans and reveals information concerning the conformational structure of the AP33 epitope, its role in viral replication, and constraints on its molecular evolution.antibody ͉ immunity ͉ vaccine ͉ viral envelope

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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In vitro selection of a neutralization-resistant hepatitis C virus escape mutant

Gal-Tanamy

Keck

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology

Rodrigues

Soares

Guerreiro

et al. 2015

Biotechnology Journal

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Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus-like particles, vectored vaccines and chimeric vaccines requires the use - and often the development - of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture.

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Chimeric hepatitis B virus/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine

et al. 2013

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The development of a prophylactic vaccine against hepatitis C virus (HCV) has become an important medical priority, because 3-4 million new HCV infections are thought to occur each year worldwide. Hepatitis B virus (HBV) is another major human pathogen, but infections with this virus can be prevented with a safe, efficient vaccine, based on the remarkable ability of the envelope protein (S) of this virus to self-assemble into highly immunogenic subviral particles. Chimeric HBV-HCV envelope proteins in which the N-terminal transmembrane domain of S was replaced with the transmembrane domain of the HCV envelope proteins (E1 or E2) were efficiently coassembled with the wild-type HBV S protein into subviral particles. These chimeric particles presented the full-length E1 and E2 proteins from a genotype 1a virus in an appropriate conformation for formation of the E1-E2 heterodimer. Produced in stably transduced Chinese hamster ovary cells and used to immunize New Zealand rabbits, these particles induced a strong specific antibody (Ab) response against the HCV and HBV envelope proteins in immunized animals. Sera containing anti-E1 or anti-E2 Abs elicited by these particles neutralized infections with HCV pseudoparticles and cellcultured viruses derived from different heterologous 1a, 1b, 2a, and 3 strains. Moreover, the anti-hepatitis B surface response induced by these chimeric particles was equivalent to the response induced by a commercial HBV vaccine. Conclusions: Our results provide support for approaches based on the development of bivalent HBV-HCV prophylactic vaccine candidates potentially able to prevent initial infection with either of these two hepatotropic viruses. (HEPATOLOGY 2013;57:1303-1313 C hronic hepatitis C virus (HCV) infection is a major public health problem affecting more than 170 million people worldwide. 1 Three to four million new infections are thought to occur each year and a prevalence of 10%-30% has been reported in countries in which this virus is highly endemic, including Egypt, which has the highest HCV prevalence in the world. 2 HCV infection is one of the leading causes of chronic liver disease; it is associated with a high risk of cirrhosis and hepatocellular carcinoma and is the major indication for liver transplantation in industrialized countries. Provided it is detected sufficiently early, progression to severe disease can be prevented by treatment with a combination of pegylated interferon (IFN)-a and ribavirin, in some cases supplemented with recently approved nonstructural protein 3/4A protease inhibitors. 3 This triple therapy yields a sustained virologic response, but is very expensive and may be associated with drug-drug interactions and severe side effects. Therefore, the development of a prophylactic vaccine against HCV is a major medical priority. However, the development of such a vaccine

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Definition of a Conserved Immunodominant Domain on Hepatitis C Virus E2 Glycoprotein by Neutralizing Human Monoclonal Antibodies

Cited by 109 publications

References 23 publications

In vitro selection of a neutralization-resistant hepatitis C virus escape mutant

In vitro selection of a neutralization-resistant hepatitis C virus escape mutant

Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology

Chimeric hepatitis B virus/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine

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