The Pneumovirinae fusion (F) protein: A common target for vaccines and antivirals

Melero, José A.; Más, Vicente

doi:10.1016/j.virusres.2015.02.024

Cited by 28 publications

(37 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As with the influenza virus, continuous surveillance may be needed to detect new emergent genotypes and to assess their immediate effect in susceptible populations. We have recently described that genetic variations are present in the three RSV surface proteins [16], including not only G protein, but also the fusion (F) protein, which is the major determinant for the host’s immune response, and the main target for antiviral therapy and vaccination strategies [36]. Some of these genomic variations in the viral genome might impact the pathogenic process and the disease, and thus need to be explored beyond genotype classification.…”

Section: Discussionmentioning

confidence: 99%

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

Espinosa

Martín

Torres

et al. 2017

IJMS

View full text Add to dashboard Cite

Abstract:The clinical impact of viral factors (types and viral loads) during respiratory syncytial virus (RSV) infection is still controversial, especially regarding newly described genotypes. In this study, infants with RSV bronchiolitis were recruited to describe the association of these viral factors with severity of infection. RSV antigenic types, genotypes, and viral loads were determined from hospitalized patients at Hospital Roberto del Río, Santiago, Chile. Cases were characterized by demographic and clinical information, including days of lower respiratory symptoms and severity. A total of 86 patients were included: 49 moderate and 37 severe cases. During 2013, RSV-A was dominant (86%). RSV-B predominated in 2014 (92%). Phylogenetic analyses revealed circulation of GA2, Buenos Aires (BA), and Ontario (ON) genotypes. No association was observed between severity of infection and RSV group (p = 0.69) or genotype (p = 0.87). After a clinical categorization of duration of illness, higher RSV genomic loads were detected in infants evaluated earlier in their disease (p < 0.001) and also in infants evaluated later, but coursing a more severe infection (p = 0.04). Although types and genotypes did not associate with severity in our children, higher RSV genomic loads and delayed viral clearance in severe patients define a group that might benefit from new antiviral therapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

Espinosa

Martín

Torres

et al. 2017

IJMS

View full text Add to dashboard Cite

show abstract

“…The G glycoprotein is heavily glycosylated with multiple O - and N -linked sugar chains, resembling mucins [10], and serves as the putative viral attachment protein via interactions with cell-surface factors such as proteoglycans [11]. Finally, the fusion (F) glycoprotein mediates fusion of the viral and cellular membranes to allow entry of the viral ribonucleoprotein into the cell cytoplasm and thus initiate a new infectious cycle [12,13]. …”

Section: Introductionmentioning

confidence: 99%

Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

et al. 2016

Self Cite

View full text Add to dashboard Cite

Human metapneumovirus (hMPV) is a paramyxovirus that is a common cause of bronchiolitis and pneumonia in children less than five years of age. The hMPV fusion (F) glycoprotein is the primary target of neutralizing antibodies and is thus a critical vaccine antigen. To facilitate structure-based vaccine design, we stabilized the ectodomain of the hMPV F protein in the postfusion conformation and determined its structure to a resolution of 3.3 Å by X-ray crystallography. The structure resembles an elongated cone and is very similar to the postfusion F protein from the related human respiratory syncytial virus (hRSV). In contrast, significant differences were apparent with the postfusion F proteins from other paramyxoviruses, such as human parainfluenza type 3 (hPIV3) and Newcastle disease virus (NDV). The high similarity of hMPV and hRSV postfusion F in two antigenic sites targeted by neutralizing antibodies prompted us to test for antibody cross-reactivity. The widely used monoclonal antibody 101F, which binds to antigenic site IV of hRSV F, was found to cross-react with hMPV postfusion F and neutralize both hRSV and hMPV. Despite the cross-reactivity of 101F and the reported cross-reactivity of two other antibodies, 54G10 and MPE8, we found no detectable cross-reactivity in the polyclonal antibody responses raised in mice against the postfusion forms of either hMPV or hRSV F. The postfusion-stabilized hMPV F protein did, however, elicit high titers of hMPV-neutralizing activity, suggesting that it could serve as an effective subunit vaccine. Structural insights from these studies should be useful for designing novel immunogens able to induce wider cross-reactive antibody responses.

show abstract

“…The G glycoprotein was originally described as the receptor-binding protein (17) that binds to cell surface proteoglycans (18)(19)(20). The fusion (F) glycoprotein mediates fusion of the viral and cell membranes to allow entry of the virus ribonucleoprotein into the cell cytoplasm and initiation of a new infectious cycle (21). The F and G glycoproteins, expressed from vaccinia virus recombinants, are the only antigens able to induce neutralizing antibodies and confer longlived protection against hRSV challenge in mice and cotton rats (22,23), with F being more efficient than G (24).…”

mentioning

confidence: 99%

Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses

Palomo

Más

Thom

et al. 2016

J Virol

Self Cite

View full text Add to dashboard Cite

Human respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates. IMPORTANCEProtection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion F (found after membrane fusion) is also able to induce neutralizing antibodies and protect against infection. In addition, a monomeric form of hRSV F that shares epitopes with prefusion F was recently reported. Since each of the indicated forms of hRSV F may have advantages and disadvantages for the development of safe and efficacious subunit vaccines, a direct comparison of the immunogenic properties and protective efficacies of the different forms of hRSV F was made in a mouse model. The results obtained show important differences between the noted immunogens that should be borne in mind when considering the development of hRSV vaccines. H uman respiratory syncytial virus (RSV) (hRSV) is the most frequent cause of severe lower respiratory tract infections (bronchiolitis and pneumonia) in infants and young children throughout the world. It is estimated that each year, the virus causes severe disease in ϳ34 million children Ͻ5 years of age, with Ͼ3.5 million requiring hospitalization, and is responsible for 66,000 to 199,000 deaths, mainly in developing ...

show abstract

The Pneumovirinae fusion (F) protein: A common target for vaccines and antivirals

Cited by 28 publications

References 91 publications

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses

Contact Info

Product

Resources

About