title: Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?
abstract: 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.
  
  
  OBJECTIVE
  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 values at certain sites predictive of positive selection. Since these sites cluster preferentially in the C-terminal third of the G protein, like certain epitopes recognized by murine antibodies, it was proposed that immune (antibody) selection might be driving the apparent positive selection, analogous to the antigenic drift observed in the influenza virus hemagglutinin (HA). However, careful antigenic and genetic comparison of the G glycoprotein does not provide evidence of antigenic drift in the G molecule, in agreement with recently published data which did not indicate antigenic drift in the G protein with human sera. Alternative explanations to the immune-driven selection hypothesis are offered to account for the high level of G-protein genetic diversity highlighted in this study.
authors.affiliation: Unidad de Biología Viral, Centro Nacional de Microbiología, Madrid, Spain CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Alfonsina
authors.initials: A
authors.lastname: Trento
authors.affiliation: Departamento de Investigación en Virología, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá, Panama.
authors.forename: Leyda
authors.initials: L
authors.lastname: Ábrego
authors.affiliation: Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rodriguez-Fernandez
authors.affiliation: Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: González-Sánchez
authors.affiliation: Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: González-Martínez
authors.affiliation: Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Delfraro
authors.affiliation: Departamento de Investigación en Virología, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá, Panama.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascale
authors.affiliation: Sección Virología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Juan
authors.initials: J
authors.lastname: Arbiza
authors.affiliation: Unidad de Biología Viral, Centro Nacional de Microbiología, Madrid, Spain CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain jmelero@isciii.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Melero
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D000940:Antigenic Variation; D017124:Conserved Sequence; D000939:Epitopes / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D019143:Evolution, Molecular; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D018357:Respiratory Syncytial Virus Infections / Q000821:virology*; D018113:Respiratory Syncytial Virus, Human / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000276:immunology; D016415:Sequence Alignment; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins