Antigenic Structure of Human Respiratory Syncytial Virus Fusion Glycoprotein

López, Juan A.; Bustos, Regla; Örvell, Claes; Berois, Mabel; Arbiza, Juan; Garcı́a-Barreno, Blanca; Melero, José A.

doi:10.1128/jvi.72.8.6922-6928.1998

Cited by 110 publications

(40 citation statements)

References 44 publications

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“…Although we do not know the exact nature of the antigenic precursor source of epitope F249-258, it must include a portion of the F protein harbouring the epitope, which is interestingly located near important antigenic sites for neutralising antibodies. 24 Our findings have important implications for RSV vaccine studies as they open the possibility of priming RSV-specific CTLs and antibodies with a non-infectious agent.…”

Section: Cross-priming Of Cd8 þ T Lymphocytes Specific For F249-258 Imentioning

confidence: 74%

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

et al. 2012

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Respiratory syncytial virus causes lower respiratory tract infections in infancy and old age, affecting also immunocompromised patients. The viral fusion protein is an important vaccine candidate eliciting antibody and cell-mediated immune responses. CD8 þ cytotoxic T lymphocytes (CTLs) are known to have a role in both lung pathology and viral clearance. In BALB/c mice, the fusion protein epitope F249-258 is presented to CTLs by the murine major histocompatibility complex (MHC) class I molecule K d . In cells infected with recombinant vaccinia viruses encoding the fusion protein, F249-258 is presented by MHC class I molecules through pathways that are independent of the transporters associated with antigen processing (TAP). We have now found that F249-258 can be generated from non-infectious virus from an exogenous source. Antigen processing follows a lysosomal pathway that appears to require autophagy. As a practical consequence, inactivated virus suffices for in vivo priming of virus-specific CTLs. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children, 3 affecting also immunocompromised patients and the elderly. The fusion (F) glycoprotein of RSV is a major vaccine candidate as it is an important target for neutralising antibodies 4 and virus-specific CTLs. 5 Studies in the mouse model of human RSV have shown that CTLs have a role both in lung pathology and viral clearance. 6,7 In previous studies,

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Section: Cross-priming Of Cd8 þ T Lymphocytes Specific For F249-258 Imentioning

confidence: 74%

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

et al. 2012

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“…Structures of F proteins complexed with neutralizing antibodies have been solved for a number of pneumo-and paramyxovirus family members including RSV (Figure 3), HPIV3, and NiV. Distinct antigenic sites were identified on RSV F (Figure 4): conformation-dependent site Ø that is located at the apex of prefusion F and a dominant target for nAbs [36,[76][77][78]; sites II and IV that are present in both the pre-and postfusion F conformations [67,79]; site III that likewise exists in both F conformations, but undergoes rearrangement of secondary structure elements forming the epitope [80,81]; site V located between sites Ø and III on prefusion F [82,83]; and post-fusion F site I [84,85]. A cryo-EM structure of HPIV3 F complexed with nAb PIA174 likewise locates the binding site to the apex of the prefusion F trimer, establishing contact with residues of all three F protomers [37].…”

Section: Druggable Sites and Neutralizing Epitopesmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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“…Beeler et al [35] have identified multiple neutralizing epitopes on RSV F protein using competitive binding assays with a panel of RSV F monoclonal antibodies and monoclonal antibody resistant mutant (MARMs) and subsequently, antigenic sites I, II, IV, V and IV were mapped on RSV F [36]. A competitive ELISA was performed using monoclonal antibodies 1107, 1112, 1153, 1243 to identify neutralizing antibodies induced by the RSV F vaccine.…”

Section: Competitive Binding Of Vaccine-induced Antibody To Other Rsvmentioning

confidence: 99%

An insect cell derived respiratory syncytial virus (RSV) F nanoparticle vaccine induces antigenic site II antibodies and protects against RSV challenge in cotton rats by active and passive immunization

Raghunandan

Lü

Zhou

et al. 2014

Vaccine

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Post-infectious immunity to respiratory syncytial virus (RSV) infection results in limited protection as evidenced by the high rate of infant hospitalization in the face of high titer, maternally derived RSV-specific antibodies. By contrast, RSV fusion (F) glycoprotein antigenic site II humanized monoclonal antibodies, palivizumab and motavizumab, have been shown to reduce RSV-related hospitalization in infants. Immunogenicity and efficacy studies were conducted in cotton rats comparing a recombinant RSV F nanoparticle vaccine with palivizumab and controlled with live RSV virus intranasal immunization and, formalin inactivated RSV vaccine. Active immunization with RSV F nanoparticle vaccine containing an alum adjuvant induced serum levels of palivizumab competing antibody (PCA) greater than passive administration of 15 mg/kg palivizumab (human prophylactic dose) in cotton rats and neutralized RSV-A and RSV-B viruses. Immunization prevented detectable RSV replication in the lungs and, unlike passive administration of palivizumab, in the nasal passage of challenged cotton rats. Histology of lung tissues following RSV challenge showed no enhanced disease in the vaccinated groups in contrast to formalin inactivated 'Lot 100' vaccine. Passive intramuscular administration of RSV F vaccine-induced immune sera one day prior to challenge of cotton rats reduced viral titers by 2 or more log10 virus per gram of lung and nasal tissue and at doses less than palivizumab. A recombinant RSV F nanoparticle vaccine protected lower and upper respiratory tract against both RSV A and B strain infection and induced polyclonal palivizumab competing antibodies similar to but potentially more broadly protective against RSV than palivizumab.

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Antigenic Structure of Human Respiratory Syncytial Virus Fusion Glycoprotein

Cited by 110 publications

References 44 publications

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

Exogenous, TAP‐independent lysosomal presentation of a respiratory syncytial virus CTL epitope

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

An insect cell derived respiratory syncytial virus (RSV) F nanoparticle vaccine induces antigenic site II antibodies and protects against RSV challenge in cotton rats by active and passive immunization

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