The Comparative Genomics of Human Respiratory Syncytial Virus Subgroups A and B: Genetic Variability and Molecular Evolutionary Dynamics

Tan, Lydia; Coenjaerts, Frank E. J.; Houspie, Lieselot; Viveen, Marco C.; Bleek, Grada M. van; Wiertz, Emmanuel J. H. J.; Martin, Darren P.; Lemey, Philippe

doi:10.1128/jvi.03278-12

Cited by 95 publications

(95 citation statements)

References 78 publications

(92 reference statements)

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“…The higher genetic variability of group A strains may partially account for their more frequent global appearance due to their greater genetic plasticity (Coggins et al, 1998), although the overall ratio of dN/dS suggests that the majority of substitutions are neutral. Therefore, the high variability found in the G gene is not entirely driven by host immunity evasion (Tan et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

A molecular epidemiological study of human respiratory syncytial virus in Croatia, 2011–2014

Slović

Ivancic-Jelecki

Ljubin‐Sternak

et al. 2016

Infection, Genetics and Evolution

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Section: Discussionmentioning

confidence: 99%

A molecular epidemiological study of human respiratory syncytial virus in Croatia, 2011–2014

Slović

Ivancic-Jelecki

Ljubin‐Sternak

et al. 2016

Infection, Genetics and Evolution

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“…Antigenic differences between the two subgroups of HRSV are predominantly mediated by the highly variable G gene (10) and might facilitate evasion of host immune responses (43). Despite these differences, infections with HRSV of either subgroup cause indistinguishable disease (1).…”

Section: Discussionmentioning

confidence: 99%

“…The glyco-(G) proteins facilitate virus attachment and entry (1,7), and the F glycoprotein is an important target of virus neutralizing antibodies (8). Molecular epidemiological studies have identified two HRSV subgroups (A and B), which cause indistinguishable disease and cocirculate during, or alternate between, yearly outbreaks (9,10).…”

mentioning

confidence: 99%

Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Lemon

Nguyen

Ludlow

et al. 2015

J Virol

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Human respiratory syncytial virus (HRSV) is IMPORTANCEVirology as a discipline has depended on monitoring cytopathic effects following virus culture in vitro. However, wild-type viruses isolated from patients often do not cause significant changes to infected cells, necessitating blind passage. This can lead to genetic and phenotypic changes and the generation of high-titer, laboratory-adapted viruses with diminished virulence in animal models of disease. To address this, we determined the genome sequence of an unpassaged human respiratory syncytial virus from a sample obtained directly from an infected infant, assembled a molecular clone, and recovered a wild-type recombinant virus. Addition of a gene encoding enhanced green fluorescent protein allowed this wild-type virus to be tracked in primary human cells and living animals in the absence of significant cytopathic effects. Imaging of fluorescent cells proved to be a highly valuable tool for monitoring the spread of virus and may help improve assays for evaluating novel intervention strategies. H uman respiratory syncytial virus (HRSV) is the most important viral cause of respiratory tract disease in infants (1). HRSV infections are observed during seasonal outbreaks in winter or during the rainy season in the tropics (2). The virus usually causes a self-limiting upper respiratory tract (URT) infection, resulting in rhinorrhea and other common cold-like clinical signs (3). However, in a minority of cases the infection can also spread to the lower respiratory tract (LRT), resulting in severe pneumonia or bronchiolitis. Risk factors for developing severe LRT infections include prematurity, pulmonary or cardiac disease, compromised immunity, and old age (4). Current treatment options are limited, although a monoclonal antibody directed against the fusion (F) glycoprotein has been developed for prophylactic use (5). Despite significant efforts in vaccine development over the past 50 years, no HRSV vaccines are currently licensed (6). Limited availability of natural animal models of disease adds to the challenge of developing vaccines and antivirals.HRSV is a member of the family Paramyxoviridae, subfamily Pneumovirinae, genus Pneumovirus (1). It is an enveloped virus with a negative-sense, single-stranded RNA genome containing 10 transcription units. The glyco-(G) proteins facilitate virus attachment and entry (1, 7), and the F glycoprotein is an important target of virus neutralizing antibodies (8). Molecular epidemiological studies have identified two HRSV subgroups (A and B),

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“…Of these envelope glycoproteins, only the RSV F protein is indispensable for viral replication in vitro (9). It is the most conserved RSV glycoprotein and also the main target of neutralizing antibodies and vaccine development (10,11). Initially, the RSV F protein assembles into a homotrimeric, metastable prefusion conformation that rearranges to a highly stable postfusion conformation during fusion of the viral and target cell membrane or spontaneously (12).…”

mentioning

confidence: 99%

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

Leemans

Schryver

Gucht

et al. 2017

J Virol

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Respiratory syncytial virus (RSV) infections remain a major cause of respiratory disease and hospitalizations among infants. Infection recurs frequently and establishes a weak and short-lived immunity. To date, RSV immunoprophylaxis and vaccine research is mainly focused on the RSV fusion (F) protein, but a vaccine remains elusive. The RSV F protein is a highly conserved surface glycoprotein and is the main target of neutralizing antibodies induced by natural infection. Here, we analyzed an internalization process of antigen-antibody complexes after binding of RSV-specific antibodies to RSV antigens expressed on the surface of infected cells. The RSV F protein and attachment (G) protein were found to be internalized in both infected and transfected cells after the addition of either RSV-specific polyclonal antibodies (PAbs) or RSV glycoprotein-specific monoclonal antibodies (MAbs), as determined by indirect immunofluorescence staining and flow-cytometric analysis. Internalization experiments with different cell lines, well-differentiated primary bronchial epithelial cells (WD-PBECs), and RSV isolates suggest that antibody internalization can be considered a general feature of RSV. More specifically for RSV F, the mechanism of internalization was shown to be clathrin dependent. All RSV F-targeted MAbs tested, regardless of their epitopes, induced internalization of RSV F. No differences could be observed between the different MAbs, indicating that RSV F internalization was epitope independent. Since this process can be either antiviral, by affecting virus assembly and production, or beneficial for the virus, by limiting the efficacy of antibodies and effector mechanism, further research is required to determine the extent to which this occurs in vivo and how this might impact RSV replication.IMPORTANCE Current research into the development of new immunoprophylaxis and vaccines is mainly focused on the RSV F protein since, among others, RSV F-specific antibodies are able to protect infants from severe disease, if administered prophylactically. However, antibody responses established after natural RSV infections are poorly protective against reinfection, and high levels of antibodies do not always correlate with protection. Therefore, RSV might be capable of interfering, at least partially, with antibody-induced neutralization. In this study, a process through which surface-expressed RSV F proteins are internalized after interaction with RSVspecific antibodies is described. One the one hand, this antigen-antibody complex internalization could result in an antiviral effect, since it may interfere with virus par-

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The Comparative Genomics of Human Respiratory Syncytial Virus Subgroups A and B: Genetic Variability and Molecular Evolutionary Dynamics

Cited by 95 publications

References 78 publications

A molecular epidemiological study of human respiratory syncytial virus in Croatia, 2011–2014

A molecular epidemiological study of human respiratory syncytial virus in Croatia, 2011–2014

Recombinant Subgroup B Human Respiratory Syncytial Virus Expressing Enhanced Green Fluorescent Protein Efficiently Replicates in Primary Human Cells and Is Virulent in Cotton Rats

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

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