Structure and Function of Respiratory Syncytial Virus Surface Glycoproteins

McLellan, Jason S.; Ray, William C.; Peeples, Mark E.

doi:10.1007/978-3-642-38919-1_4

Cited by 227 publications

(301 citation statements)

References 102 publications

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“…HRSV Glycoprotein protein (G): this protein is involved in virus attachment 114 and it also exists as a secreted form, which prevents opsonization and neutralization of hRSV by anti-G specific antibodies. Moreover, the secreted form of the G protein has a chemokine-like motif (CX3C) that competes with fractalkine (CX3CL1) in binding to its receptor CX3CR1, thus reducing the CX3CR1 C T cells response.…”

Section: Role Of Hrsv Proteins In Immunomodulationmentioning

confidence: 99%

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

et al. 2016

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Human Respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are the two major etiological viral agents of lower respiratory tract diseases, affecting mainly infants, young children and the elderly. Although the infection of both viruses trigger an antiviral immune response that mediate viral clearance and disease resolution in immunocompetent individuals, the promotion of long-term immunity appears to be deficient and reinfection are common throughout life. A possible explanation for this phenomenon is that hRSV and hMPV, can induce aberrant T cell responses, which leads to exacerbated lung inflammation and poor T and B cell memory immunity. The modulation of immune response exerted by both viruses include different strategies such as, impairment of immunological synapse mediated by viral proteins or soluble factors, and the induction of pro-inflammatory cytokines by epithelial cells, among others. All these viral strategies contribute to the alteration of the adaptive immunity in order to increase the susceptibility to reinfections.In this review, we discuss current research related to the mechanisms underlying the impairment of T and B cell immune responses induced by hRSV and hMPV infection. In addition, we described the role each virulence factor involved in immune modulation caused by these viruses.

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Section: Role Of Hrsv Proteins In Immunomodulationmentioning

confidence: 99%

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

et al. 2016

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“…The F protein of RSV is a 574 amino acids class I fusion glycoprotein similar to influenza virus hemagglutinin and HIV -1 envelope glycoprotein 11,12) . It is synthesized as a precursor F 0 and cleaved by the furin -like host protease to produce F 1 and F 2 subunits 13,14) .…”

Section: F Proteinmentioning

confidence: 99%

“…The mature protein contains three copies of two polypeptides (F 1 and F 2 ). After initially folding into a metastable prefusion conformation (pre -F), RSV F undergoes a structural change naturally or in the process of infection, and eventually acquires a stable postfusion conformation (post -F) 12) . Recently, cryoelectron tomography of cell culturegrown RSV has revealed that pre -F and post -F are present on the virion surface.…”

Section: F Proteinmentioning

confidence: 99%

Neutralizing epitopes of RSV and palivizumab resistance in Japan

Hashimoto¹,

Hosoya²

2017

FJMS

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Respiratory Syncytial Virus (RSV) is one of the most important viral pathogen related to acute lower respiratory infection in young children. The virus surface envelope contains the G, F, and SH proteins as spike proteins. The F protein is considered to be a major antigenic target for the neutralizing (NT) epitope as only the F protein is essential for cell infection among the three viral envelope proteins, and it is more highly conserved than the G protein. Recently, four antigenic targets related to NT activity have been reported ; site I, site II, site IV, and site zero (0). Site II is the target for palivizumab used throughout the world to suppress severe RSV infection as passive immunity in high -risk children since 1998. Under the recent conditions in which indications for palivizumab administered subjects are being expanded, palivizumab -resistant mutations have been confirmed overseas in children with RSV infection, although they remain infrequent. Therefore, continuous genetic analysis of the palivizumab -binding region of the F protein is necessary. In addition, as vaccine development progresses, RSV infection control is expected to improve greatly over the next decade.

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“…Anchored by a hydrophobic transmembrane domain at its C terminus, F 1 comprises the hallmark features of a type 1 fusion protein, having a hydrophobic fusion peptide (FP) at the N terminus and two major heptad repeats, A and B (HRA and HRB, respectively), that ultimately refold to form the hyperstable six-helix bundle (6HB) that constitutes the fusion core of the postfusion structure. Triggering of the protein is thought to be provoked by receptor engagement, which prompts the release of the hydrophobic FP into the target membrane and the accompanied elongation of the HRA helices beyond the head of the protein (10,11). Refolding of HRA and HRB brings the viral and host membranes into close proximity, resulting in membrane fusion driven by the energy difference between the pre-and postfusion conformations of the protein (10,11).…”

mentioning

confidence: 99%

“…Triggering of the protein is thought to be provoked by receptor engagement, which prompts the release of the hydrophobic FP into the target membrane and the accompanied elongation of the HRA helices beyond the head of the protein (10,11). Refolding of HRA and HRB brings the viral and host membranes into close proximity, resulting in membrane fusion driven by the energy difference between the pre-and postfusion conformations of the protein (10,11). In addition to facilitating the fusion of viral and cellular membranes, cell surface F protein also drives fusion between infected and neighboring cells, resulting in the formation of large multinucleated cells, or syncytia (12,13).…”

mentioning

confidence: 99%

The Heptad Repeat C Domain of the Respiratory Syncytial Virus Fusion Protein Plays a Key Role in Membrane Fusion

Bermingham

Chappell

Watterson

et al. 2018

J Virol

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Respiratory syncytial virus (RSV) mediates host cell entry through the fusion (F) protein, which undergoes a conformational change to facilitate the merger of viral and host lipid membrane envelopes. The RSV F protein comprises a trimer of disulfide-bonded F 1 and F 2 subunits that is present on the virion surface in a metastable prefusion state. This prefusion form is readily triggered to undergo refolding to bring two heptad repeats (heptad repeat A [HRA] and HRB) into close proximity to form a six-helix bundle that stabilizes the postfusion form and provides the free energy required for membrane fusion. This process can be triggered independently of other proteins. Here, we have performed a comprehensive analysis of a third heptad repeat region, HRC (amino acids 75 to 97), an amphipathic ␣-helix that lies at the interface of the prefusion F trimer and is a major structural feature of the F 2 subunit. We performed alanine scanning mutagenesis from Lys-75 to Met-97 and assessed all mutations in transient cell culture for expression, proteolytic processing, cell surface localization, protein conformation, and membrane fusion. Functional characterization revealed a striking distribution of activity in which fusion-increasing mutations localized to one side of the helical face, while fusion-decreasing mutations clustered on the opposing face. Here, we propose a model in which HRC plays a stabilizing role within the globular head for the prefusion F trimer and is potentially involved in the early events of triggering, prompting fusion peptide release and transition into the postfusion state.IMPORTANCE RSV is recognized as the most important viral pathogen among pediatric populations worldwide, yet no vaccine or widely available therapeutic treatment is available. The F protein is critical for the viral replication process and is the major target for neutralizing antibodies. Recent years have seen the development of prefusion stabilized F protein-based approaches to vaccine design. A detailed understanding of the specific domains and residues that contribute to protein stability and fusion function is fundamental to such efforts. Here, we present a comprehensive mutagenesis-based study of a region of the RSV F 2 subunit (amino acids 75 to 97), referred to as HRC, and propose a role for this helical region in maintaining the delicate stability of the prefusion form.KEYWORDS respiratory syncytial virus, fusion, membrane fusion, mutagenesis, heptad repeat R espiratory syncytial virus (RSV) is widely considered the most significant viral pediatric pathogen worldwide. Belonging to the Pneumovirinae family, RSV causes substantial morbidity and mortality worldwide, with an estimated 33.8 million acute lower respiratory tract infections per year in children under 5 years of age, and has been linked to almost 200,000 deaths annually, 99% of which are in developing countries (1, 2). RSV is also recognized as an important pathogen of high-risk adult and elderly populations (3). Despite this, no targeted drug or vaccin...

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Structure and Function of Respiratory Syncytial Virus Surface Glycoproteins

Cited by 227 publications

References 102 publications

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

Neutralizing epitopes of RSV and palivizumab resistance in Japan

The Heptad Repeat C Domain of the Respiratory Syncytial Virus Fusion Protein Plays a Key Role in Membrane Fusion

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