Rapid Spread and Diversification of Respiratory Syncytial Virus Genotype ON1, Kenya

Agoti, Charles N.; Otieno, James R.; Gitahi, Caroline W.; Cane, Patricia A.; Nokes, D. James

doi:10.3201/eid2006.131438

Cited by 79 publications

(120 citation statements)

References 35 publications

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“…Due to limitations of RSV animal models, direct-contact transmission studies with RSV are not reported but might provide further clues to the selective advantage of the duplication in BA strain G genes if they could be achieved. ON1 subgroup A RSV strains also harboring a duplication in the G protein are beginning to predominate among circulating RSV strains (11)(12)(13). The duplicated region in G of ON1 strains encodes 11 additional potential O-glycosylation sites (10).…”

Section: Discussionmentioning

confidence: 99%

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Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein

Hotard

Laikhter

Brooks

et al. 2015

J Virol

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There are two subgroups of respiratory syncytial virus (RSV), A and B, and within each subgroup, isolates are further divided into clades. Several years ago, multiple subgroup B isolates which contained a duplication of 60 nucleotides in the glycoprotein (G) gene were described. These isolates were given a new clade designation of BA based on the site of isolation, Buenos Aires, Argentina. BA RSV strains have since become the predominant circulating clade of RSV B viruses. We hypothesized that the duplicated region in G serves to enhance the function of G in the virus life cycle. We generated recombinant viruses that express a consensus BA G gene or a consensus BA G gene lacking the duplication (G ⌬dup ). We determined that the duplicated region functions during virus attachment to cells. Additionally, we showed that in vitro, the virus containing the duplication has a fitness advantage compared to the virus without the duplication. Our data demonstrate that the duplicated region in the BA strain G protein augments virus attachment and fitness. IMPORTANCERespiratory syncytial virus (RSV) is an important pathogen for infants for which there is no vaccine. Different strains of RSV circulate from year to year, and the predominating strains change over time. Subgroup B RSV strains with a duplication in the attachment glycoprotein (G) emerged and then became the dominant B genotype. We found that a recombinant virus harboring the duplication bound more efficiently to cells and was more fit than a recombinant strain lacking the duplication. Our work advances a mechanism for an important natural RSV mutation. R espiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants worldwide. The attachment glycoprotein (G) is the most variable RSV protein (1). The G protein is a type II transmembrane protein, consisting of an N-terminal cytoplasmic tail, a transmembrane domain, and a Cterminal ectodomain. The ectodomain of RSV G is characterized by two hypervariable, mucin-like domains which flank a central conserved region. As the name implies, most of the variability between G proteins of different strains is located in the hypervariable regions. The final 270 nucleotides (nt) of the G gene, encompassing part of the second hypervariable region, are commonly used to determine classification of RSV strains as belonging to subgroup A or B. Phylogenetic analysis of this region of G also classifies clades within each subgroup (2).In the late 1990s, several isolates of RSV subgroup B strains from Buenos Aires, Argentina, were identified to contain an as yet undescribed duplication of 60 nt in the second hypervariable region of the G gene (3). The duplication was exact, such that an additional sequence of 20 amino acids followed the first run of those residues. The specific genotype of strains containing the duplication was termed "BA" for Buenos Aires, the site of the first described isolation events (4). Since the identification of those original isolates, B strains of RSV harbo...

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Section: Discussionmentioning

confidence: 99%

“…These strains, termed "ON1" for their original isolation in Ontario, Canada, were first described in 2012 (10). As with BA strains, since their original description, ON1 RSV strains have been isolated globally and are trending toward predominating among circulating A strains (11)(12)(13).…”

mentioning

confidence: 99%

Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein

Hotard

Laikhter

Brooks

et al. 2015

J Virol

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“…The RNA-dependent replication cycle of RSV is significant because it is error prone and there is no proofreading mechanism. This allows for the rapid generation of single nucleotide polymorphisms (SNPs) and other mutations which allow for changes in virus virulence and avoidance of potential future antiviral agents or vaccines (15).…”

Section: The Virus Prone To Genetic Changementioning

confidence: 99%

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

2017

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SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

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“…Recent publications have drawn attention to the shift from "multiple genotype circulation to prolonged circulation of predominant genotypes," as seen in Belgium between 1996 and 2011 (30). In addition, a novel GA2 variant with a 72-nt duplication, named ON1 and first detected in Ontario (Canada) in December 2010 (31), has spread rapidly worldwide (32)(33)(34), exacerbating the current dominance of the GA2 genotype.…”

Section: Evolution and Dominance Of Group A Genotypes Over Timementioning

confidence: 99%

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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Rapid Spread and Diversification of Respiratory Syncytial Virus Genotype ON1, Kenya

Abstract: Surveillance of this new genotype helps clarify the mechanisms of rapid emergence of respiratory viruses.

Cited by 79 publications

References 35 publications

Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein

Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

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

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