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Identification of multiple protective epitopes (protectopes) in the central conserved domain of a prototype human respiratory syncytial virus G protein.

ABSTRACT: A recombinant fusion protein (BBG2Na) comprising the central conserved domain of the respiratory syncytial virus subgroup A (RSV-A) (Long) G protein (residues 130 to 230) and an albumin binding domain of streptococcal protein G was shown previously to protect mouse upper (URT) and lower (LRT) respiratory tracts against intranasal RSV challenge (U. F. Power, H. Plotnicky-Gilquin, T. Huss, A. Robert, M. Trudel, S. Stahl, M. Uhlén, T. N. Nguyen, and H. Binz, Virology 230:155-166, 1997). Panels of monoclonal antibodies (MAbs) and synthetic peptides were generated to facilitate dissection of the structural elements of this domain implicated in protective efficacy. All MAbs recognized native RSV-A antigens, and five linear B-cell epitopes were identified; these mapped to residues 152 to 163, 165 to 172, 171 to 187 (two overlapping epitopes), and 196 to 204, thereby covering the highly conserved cysteine noose domain. Antibody passive-transfer and peptide immunization studies revealed that all epitopes were implicated in protection of the LRT, but not likely the URT, against RSV-A challenge. Pepscan analyses of anti-RSV-A and anti-BBG2Na murine polyclonal sera revealed lower-level epitope usage within the central conserved region in the former, suggesting diminished immunogenicity of the implicated epitopes in the context of the whole virus. However, Pepscan analyses of RSV-seropositive human sera revealed that all of the murine B-cell protective epitopes (protectopes) that mapped to the central conserved domain were recognized in man. Should these murine protectopes also be implicated in human LRT protection, their clustering around the highly conserved cysteine noose region will have important implications for the development of RSV vaccines.

SUBMITTER: Plotnicky-Gilquin H

PROVIDER: S-EPMC112622 | biostudies-literature | 1999 Jul

REPOSITORIES: biostudies-literature

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Identification of multiple protective epitopes (protectopes) in the central conserved domain of a prototype human respiratory syncytial virus G protein.

Plotnicky-Gilquin H H Goetsch L L Huss T T Champion T T Beck A A Haeuw J F JF Nguyen T N TN Bonnefoy J Y JY Corvaïa N N Power U F UF

Journal of virology 19990701 7

A recombinant fusion protein (BBG2Na) comprising the central conserved domain of the respiratory syncytial virus subgroup A (RSV-A) (Long) G protein (residues 130 to 230) and an albumin binding domain of streptococcal protein G was shown previously to protect mouse upper (URT) and lower (LRT) respiratory tracts against intranasal RSV challenge (U. F. Power, H. Plotnicky-Gilquin, T. Huss, A. Robert, M. Trudel, S. Stahl, M. Uhlén, T. N. Nguyen, and H. Binz, Virology 230:155-166, 1997). Panels of m ...[more]

PMID: 10364313

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Project description:Respiratory syncytial virus (RSV) is a top cause of severe lower respiratory tract disease and mortality in infants and the elderly. Currently, no vaccine or effective treatment exists for RSV. The RSV G glycoprotein mediates viral attachment to cells and contributes to pathogenesis by modulating host immunity through interactions with the human chemokine receptor CX3CR1. Antibodies targeting the RSV G central conserved domain are protective in both prophylactic and postinfection animal models. Here, we describe the crystal structure of the broadly neutralizing human monoclonal antibody 3G12 bound to the RSV G central conserved domain. Antibody 3G12 binds to a conformational epitope composed of highly conserved residues, explaining its broad neutralization activity. Surprisingly, RSV G complexed with 3G12 adopts a distinct conformation not observed in previously described RSV G-antibody structures. Comparison to other structures reveals that the RSV G central conserved domain is flexible and can adopt multiple conformations in the regions flanking the cysteine noose. We also show that restriction of RSV G flexibility with a proline mutation abolishes binding to antibody 3G12 but not antibody 3D3, which recognizes a different conformation of RSV G. Our studies provide new insights for rational vaccine design, indicating the importance of preserving both the global structural integrity of antigens and local conformational flexibility at antigenic sites, which may elicit a more diverse antibody response and broader protection against infection and disease.IMPORTANCE Respiratory syncytial virus (RSV) causes severe respiratory infections in infants, young children, and the elderly, and currently, no licensed vaccine exists. In this study, we describe the crystal structure of the RSV surface glycoprotein G in complex with a broadly neutralizing human monoclonal antibody. The antibody binds to RSV G at a highly conserved region stabilized by two disulfide bonds, but it captures RSV G in a conformation not previously observed, revealing that this region is both structured and flexible. Importantly, our findings provide insight for the design of vaccines that elicit diverse antibodies, which may provide broad protection from infection and disease.

Dataset Information

Identification of multiple protective epitopes (protectopes) in the central conserved domain of a prototype human respiratory syncytial virus G protein.

Publications

Identification of multiple protective epitopes (protectopes) in the central conserved domain of a prototype human respiratory syncytial virus G protein.

Similar Datasets

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