Genetic Variability of Respiratory Syncytial Viruses (RSV) Prevalent in Southwestern China from 2006 to 2009: Emergence of Subgroup B and A RSV as Dominant Strains

Zhang, Zhiyong; Du, Lei; Chen, Xin; Zhao, Yongkun; Liu, Enmei; Yang, Xin; Zhao, Xiaodong

doi:10.1128/jcm.02258-09

Cited by 68 publications

(92 citation statements)

References 33 publications

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“…Since then, these BA strain viruses have become the prominent circulating B strains (79)(80)(81)(82)(83)(84)(85). More recently, an A strain with a 72-nucleotide duplication in the C-terminal third of its G protein has become a predominant circulating A strain (79-81, 83, 85-87).…”

Section: Discussionmentioning

confidence: 99%

Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures

Corry

Johnson

Cornwell

et al. 2016

J Virol

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All live attenuated respiratory syncytial virus (RSV) vaccines that have advanced to clinical trials have been produced in Vero cells. The attachment (G) glycoprotein in virions produced in these cells is smaller than that produced in other immortalized cells due to cleavage. These virions are 5-fold less infectious for primary well-differentiated human airway epithelial (HAE) cell cultures. Because HAE cells are isolated directly from human airways, Vero cell-grown vaccine virus would very likely be similarly inefficient at initiating infection of the nasal epithelium following vaccination, and therefore, a larger inoculum would be required for effective vaccination. We hypothesized that Vero cell-derived virus containing an intact G protein would be more infectious for HAE cell cultures. Using protease inhibitors with increasing specificity, we identified cathepsin L to be the protease responsible for cleavage. Our evidence suggests that cleavage occurs in the late endosome or lysosome during endocytic recycling. Cathepsin L activity was 100-fold greater in Vero cells than in HeLa cells. In addition, cathepsin L was able to cleave the G protein in Vero cell-grown virions but not in HeLa cell-grown virions, suggesting a difference in G-protein posttranslational modification in the two cell lines. We identified by mutagenesis amino acids important for cleavage, and these amino acids included a likely cathepsin L cleavage site. Virus containing a modified, noncleavable G protein produced in Vero cells was 5-fold more infectious for HAE cells in culture, confirming our hypothesis and indicating the value of including such a mutation in future live attenuated RSV vaccines. IMPORTANCEWorldwide, RSV is the second leading infectious cause of infant death, but no vaccine is available. Experimental live attenuated RSV vaccines are grown in Vero cells, but during production the virion attachment (G) glycoprotein is cleaved. Virions containing a cleaved G protein are less infectious for primary airway epithelial cells, the natural RSV target. In the study described here we identified the protease responsible, located the cleavage site, and demonstrated that cleavage likely occurs during endocytic recycling. Moreover, we showed that the infectivity of Vero cell-derived virus for primary airway epithelial cells is increased 5-fold if the virus contains a mutation in the G protein that prevents cleavage. The blocking of cleavage should improve RSV vaccine yield, consequently reducing production costs. Posttranslational cleavage of the fusion glycoprotein of many viruses plays an essential role in activation; however, cleavage of the RSV G protein is a novel example of a detrimental effect of cleavage on virus infectivity. In adults and teenagers, most respiratory syncytial virus (RSV) infections produce upper respiratory tract infection and symptoms. However, in infants, the immunocompromised, and the elderly, RSV has the potential to cause life-threatening lower respiratory tract infection (1-4). Worldwide, in 2010 ...

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Section: Discussionmentioning

confidence: 99%

Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures

Corry

Johnson

Cornwell

et al. 2016

J Virol

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“…Several studies on the presence of HRSV variants have been performed in other Asian countries, such as China, Japan, Thailand, and India [15][16][17][18]. While most of these studies have confirmed the spread of the novel 1999 Buenos Aires (BA)-like viruses in these countries, others have presented evidence on the emergence of genotypically novel variants within the HRSV subgroups that are circulating domestically [17,19,20].…”

Section: Introductionmentioning

confidence: 94%

Prevalence and genetic characterization of respiratory syncytial virus (RSV) in hospitalized children in Korea

et al. 2012

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Human respiratory syncytial virus (HRSV) is the most common respiratory pathogen among infants and young children. To investigate the prevalence and genetic characteristics of HRSVs circulating in South Korea, we analyzed medical records of patients and performed molecular analysis of the G-protein gene of viruses detected from nasopharyngeal aspirates (NPA) of admitted patients at the Pediatrics Department of Chungbuk National University Hospital from April 2008 to April 2010. Epidemiological data revealed that the prevalence of HRSV infection was high during both winter seasons (October 2008 to February 2009 and November 2009 to February 2010). Of the 297 positive NPA specimens from infants or children tested, 67% were identified as HRSV-A while 33% were HRSV-B. The HRSV subgroup B was the most dominant in December 2008, but its dominance was dramatically replaced by HRSV subgroup A strains by February 2009. Phylogenetic analysis of the G protein sequences of HRSVs revealed novel genotypes within the HRSV-A (genotype CB-A) and B (genotypes BA11 and CB-B) subgroups in South Korea in addition to other strains identified in other countries. Molecular analysis also revealed genetic variability at the C-terminal end of the G proteins of the two HRSV subgroups, suggesting selection pressure in this region, which may potentially impact immune recognition. This is the first report of these HRSV variants in South Korea, indicating active genetic evolution of HRSV strains. Therefore, this study provides information on the molecular epidemiology of current HRSVs in the country and presents data for comparative analysis with other HRSV strains circulating worldwide.

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“…The G protein is one of the targets of host immune response and thus a vaccine candidate. hRSV group B strains have been classified into 13 reported genotypes GB1, GB2, GB3, GB4, SAB1, SAB2, SAB3, SAB4, URU1, URU2, JAB1, CB1 and BA [5,8,9,21,23,25]. The BA genotype has 60 nucleotide duplication in the second hypervariable region of the G protein gene.…”

Section: Introductionmentioning

confidence: 99%

Retrospective phylogenetic analysis of circulating BA genotype of human respiratory syncytial virus with 60 bp duplication from New Delhi, India during 2007–2010

Khan

Deeba

et al. 2015

VirusDis.

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Human respiratory syncytial virus (hRSV) is the most common viral pathogen of acute lower respiratory tract infection in infants and young children. The G protein of hRSV is the trans-membrane glycoprotein that is involved in the attachment of virion with the host cell. The nasopharyngeal aspirates were subjected to RT-PCR for the second hypervariable region of the G protein gene in the present investigation. Sequencing and phylogenetic analysis revealed that all the study strains clustered within the BA genotype. The study sequences further clustered in BA-9, BA-7, BA-10 and BA-12 subgroups within the BA genotype. The G proteins of the study sequences were predicted to encode 312 and 319 amino acids. Three different N-linked glycosylation sites were observed in the deduced 93-100 amino acid region. There were 40-43 serine and threonine residues that are the potential O-linked glycosylation sites. The non-synonymous/synonymous (dN/dS) ratio was less than one indicating negative selection pressure for amino acid change in the analyzed region of the G protein. The present investigation provides information on circulating strains of BA genotype from New Delhi, India. Further elaborate investigations of the BA viruses from different regions of the world will establish the basis of the rapid global spread and evolutionary pattern of this expanding genotype.

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Genetic Variability of Respiratory Syncytial Viruses (RSV) Prevalent in Southwestern China from 2006 to 2009: Emergence of Subgroup B and A RSV as Dominant Strains

Abstract: Respiratory syncytial virus (RSV) is the most commonly identified viral agent in young children

Cited by 68 publications

References 33 publications

Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures

Preventing Cleavage of the Respiratory Syncytial Virus Attachment Protein in Vero Cells Rescues the Infectivity of Progeny Virus for Primary Human Airway Cultures

Prevalence and genetic characterization of respiratory syncytial virus (RSV) in hospitalized children in Korea

Retrospective phylogenetic analysis of circulating BA genotype of human respiratory syncytial virus with 60 bp duplication from New Delhi, India during 2007–2010

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