Location of the Epitope Recognized by Monoclonal Antibody 63G on the Primary Structure of Human Respiratory Syncytial Virus G Glycoprotein and the Ability of Synthetic Peptides Containing this Epitope to Induce Neutralizing Antibodies

Garcı́a-Barreno, Blanca; Delgado, Teresa; Åkerlind-Stopner, B.; Norrby, Erling; Melero, José A.

doi:10.1099/0022-1317-73-10-2625

Cited by 26 publications

(12 citation statements)

References 23 publications

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“…For instance, MAb 63G did not react with viruses Mon/9/91, Mad/GM2_14/12, and Mon/4/90, which have the changes P206Q, K205E, and F208P, respectively, within the stretch of amino acids where epitope 63G has been mapped (37). Note, however, that the changes F208I/L in the same region did not alter reactivity with MAb 63G.…”

Section: Evolution and Dominance Of Group A Genotypes Over Timementioning

confidence: 82%

Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?

Trento

Ábrego

Rodríguez‐Fernández

et al. 2015

J Virol

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Worldwide G-glycoprotein phylogeny of human respiratory syncytial virus (hRSV) group A sequences revealed diversification in major clades and genotypes over more than 50 years of recorded history. Multiple genotypes cocirculated during prolonged periods of time, but recent dominance of the GA2 genotype was noticed in several studies, and it is highlighted here with sequences from viruses circulating recently in Spain and Panama. Reactivity of group A viruses with monoclonal antibodies (MAbs) that recognize strain-variable epitopes of the G glycoprotein failed to correlate genotype diversification with antibody reactivity. Additionally, no clear correlation was found between changes in strain-variable epitopes and predicted sites of positive selection, despite both traits being associated with the C-terminal third of the G glycoprotein. Hence, our data do not lend support to the proposed antibody-driven selection of variants as a major determinant of hRSV evolution. Other alternative mechanisms are considered to account for the high degree of hRSV G-protein variability. H uman respiratory syncytial virus (hRSV) is recognized as the major cause of severe acute lower respiratory tract infections (ALRI) in infants and young children worldwide (1). hRSV causes annual epidemics, and reinfections are common throughout life, although they are usually less severe than the primary infections. hRSV is also an important cause of morbidity and mortality in the elderly and in adults with cardiopulmonary disease or with an impaired immune system (2). IMPORTANCE An unusual characteristic of the G glycoprotein of human respiratory syncytial virus (hRSV) is the accumulation of nonsynonymous (N) changes at higher rates than synonymous (S) changes, reaching dN/dS valueshRSV is an enveloped, nonsegmented, negative-sense RNA virus, classified in the genus Pneumovirus within the Paramyxoviridae family (for a recent review, see reference 3). The hRSV genome encodes 11 proteins, two of them being the major surface glycoproteins of the virus envelope. These are (i) the attachment (G) protein, which mediates binding of the virus to the cell surface (4), and (ii) the fusion (F) protein, which promotes fusion of the virus and cell membrane, allowing cell entry of the viral genome (5).The G protein is a type II glycoprotein synthesized as a 32-kDa polypeptide precursor of 297 to 310 amino acids (aa), depending on the strain, and modified posttranslationally by the addition of several N-linked oligosaccharides and multiple O-linked sugar chains (6). The G-protein ectodomain (from residue 67 to the C terminus) has a central conserved region (aa 163 to 189) that includes four Cys residues (residues 173, 176, 182, and 186), and it is essentially devoid of potential glycosylation sites. This conserved region is flanked by two highly variable mucin-like segments, very rich in Ser and Thr, that are potential sites of O glycosylation. The extensive glycosylation of the G protein shapes its reactivity with both murine monoclonal antibodies (M...

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Section: Evolution and Dominance Of Group A Genotypes Over Timementioning

confidence: 82%

Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?

Trento

Ábrego

Rodríguez‐Fernández

et al. 2015

J Virol

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“…These data may be useful in designing a synthetic peptide capable of inducing a group cross-reactive neutralizing and protective immune response. To date, only RSV group-specific protective synthetic peptides which mainly represent sequences adjacent to the centrally conserved region have been described (Akerlind-Stopner et al, 1990 ;Garcia-Barreno et al, 1992 ;Trudel et al, 1991 ;Simard et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Monoclonal antibody neutralization escape mutants of respiratory syncytial virus with unique alterations in the attachment (G) protein.

Walsh

Falsey

Sullender

1998

Journal of General Virology

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Five monoclonal antibody (MAb) neutralization escape mutants of respiratory syncytial virus (RSV) were produced by growing the Long strain RSV (group A virus) in the presence of a neutralizing, group cross-reactive MAb specific for the attachment protein (G). Four viruses (RSV-2, -6, -14 and -15) had amino acid replacements clustered within a highly conserved centrally located 13 amino acid region (position 164 -176). Reactivity with group Aspecific MAbs and with polyclonal anti-G serum was maintained and growth kinetics were unaffected. An

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“…MAbs 2F, 47F, and 101F specific for F protein of HRSV and MAb 63G against G protein have been previously described (27,28,45,76). They were purified from ascitic fluids by protein A-Sepharose chromatography (28).…”

Section: Methodsmentioning

confidence: 99%

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

Magro

Andreu

Gómez‐Puertas

et al. 2010

J Virol

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Human respiratory syncytial virus (HRSV) fusion (F) protein is an essential component of the virus envelope that mediates fusion of the viral and cell membranes, and, therefore, it is an attractive target for drug and vaccine development. Our aim was to analyze the neutralizing mechanism of anti-F antibodies in comparison with other low-molecular-weight compounds targeted against the F molecule. It was found that neutralization by anti-F antibodies is related to epitope specificity. Thus, neutralizing and nonneutralizing antibodies could bind equally well to virions and remained bound after ultracentrifugation of the virus, but only the former inhibited virus infectivity. Neutralization by antibodies correlated with inhibition of cell-cell fusion in a syncytium formation assay, but not with inhibition of virus binding to cells. In contrast, a peptide (residues 478 to 516 of F protein [F478-516]) derived from the F protein heptad repeat B (HRB) or the organic compound BMS-433771 did not interfere with virus infectivity if incubated with virus before ultracentrifugation or during adsorption of virus to cells at 4°C. These inhibitors must be present during virus entry to effect HRSV neutralization. These results are best interpreted by asserting that neutralizing antibodies bind to the F protein in virions interfering with its activation for fusion. Binding of nonneutralizing antibodies is not enough to block this step. In contrast, the peptide F478-516 or BMS-433771 must bind to F protein intermediates generated during virus-cell membrane fusion, blocking further development of this process.Human respiratory syncytial virus (HRSV), a member of the Pneumovirus genus of the Paramyxoviridae family, is the main cause of severe lower respiratory tract infections in very young children (36), and it is a pathogen of considerable importance in the elderly (24, 26) and in immunocompromised adults (22). Currently, there is no effective vaccine against the virus although it is known that passive administration of neutralizing antibodies to individuals at high risk is an effective immunoprophylaxis (37,38).The HRSV genome is a single-stranded negative-sense RNA molecule of approximately 15 kb that encodes 11 proteins (16, 53). Two of these proteins are the main surface glycoproteins of the virion. These are (i) the attachment (G) protein, which mediates virus binding to cells (44), and (ii) the fusion (F) protein, which promotes both fusion of the viral and cell membranes at the initial stages of the infectious cycle and fusion of the membrane of infected cells with those of adjacent cells to form characteristic syncytia (72). These two glycoproteins are the only targets of neutralizing antibodies either induced in animal models (19,63,65,70) or present in human sera (62).The G protein is a highly variable type II glycoprotein that shares neither sequence identity nor structural features with the attachment protein of other paramyxoviruses (75). It is synthesized as a precursor of about 300 amino acids (depending on the strai...

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Location of the Epitope Recognized by Monoclonal Antibody 63G on the Primary Structure of Human Respiratory Syncytial Virus G Glycoprotein and the Ability of Synthetic Peptides Containing this Epitope to Induce Neutralizing Antibodies

Cited by 26 publications

References 23 publications

Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?

Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?

Monoclonal antibody neutralization escape mutants of respiratory syncytial virus with unique alterations in the attachment (G) protein.

Neutralization of Human Respiratory Syncytial Virus Infectivity by Antibodies and Low-Molecular-Weight Compounds Targeted against the Fusion Glycoprotein

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