title: Mutating the CX3C Motif in the G Protein Should Make a Live Respiratory Syncytial Virus Vaccine Safer and More Effective.
abstract: Respiratory syncytial virus (RSV) belongs to the familyParamyxoviridaeand is the single most important cause of serious lower respiratory tract infections in young children, yet no highly effective treatment or vaccine is available. Through a CX3C chemokine motif (182CWAIC186) in the G protein, RSV binds to the corresponding chemokine receptor, CX3CR1. Since RSV binding to CX3CR1 contributes to disease pathogenesis, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), which is known to block binding to CX3CR1, might decrease disease. We studied the effect of the CX4C mutation in two strains of RSV (A2 and r19F) in a mouse challenge model. We included RSV r19F because it induces mucus production and airway resistance, two manifestations of RSV infection in humans, in mice. Compared to wild-type (wt) virus, mice infected with CX4C had a 0.7 to 1.2 log10-fold lower virus titer in the lung at 5 days postinfection (p.i.) and had markedly reduced weight loss, pulmonary inflammatory cell infiltration, mucus production, and airway resistance after challenge. This decrease in disease was not dependent on decrease in virus replication but did correspond to a decrease in pulmonary Th2 and inflammatory cytokines. Mice infected with CX4C viruses also had higher antibody titers and a Th1-biased T cell memory response at 75 days p.i. These results suggest that the CX4C mutation in the G protein could improve the safety and efficacy of a live attenuated RSV vaccine.IMPORTANCERSV binds to the corresponding chemokine receptor, CX3CR1, through a CX3C chemokine motif (182CWAIC186) in the G protein. RSV binding to CX3CR1 contributes to disease pathogenesis; therefore, we investigated whether a mutation in the CX3C motif by insertion of an alanine, A186, within the CX3C motif, mutating it to CX4C (182CWAIAC187), known to block binding to CX3CR1, might decrease disease. The effect of this mutation and treatment with the F(ab')2form of the anti-RSV G 131-2G monoclonal antibody (MAb) show that mutating the CX3C motif to CX4C blocks much of the disease and immune modulation associated with the G protein and should improve the safety and efficacy of a live attenuated RSV vaccine.
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: S
authors.initials: S
authors.lastname: Boyoglu-Barnum
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: S O
authors.initials: SO
authors.lastname: Todd
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: J
authors.initials: J
authors.lastname: Meng
authors.affiliation: University of Georgia, Odum School of Ecology, Athens, Georgia, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Barnum
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: T
authors.initials: T
authors.lastname: Chirkova
authors.affiliation: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC, Atlanta, Georgia, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Haynes
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Jadhao
authors.affiliation: University of Georgia, Department of Infectious Diseases, Animal Health Research Center, Athens, Georgia, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Tripp
authors.affiliation: Department of Veterinary Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Oomens
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, Georgia, USA larry.anderson@emory.edu.
authors.forename: L J
authors.initials: LJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D020523:Chemokines, CX3C / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D022261:Respiratory Syncytial Virus Vaccines / Q000009:adverse effects* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018417:Th1 Cells; D018418:Th2 Cells; D014613:Vaccines, Attenuated / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014779:Virus Replication
chemical_list: D000914:Antibodies, Viral; D020523:Chemokines, CX3C; D022261:Respiratory Syncytial Virus Vaccines; D014613:Vaccines, Attenuated; D019204:GTP-Binding Proteins
keywords: CX3C motif; G proteins; live attenuated vaccines; respiratory syncytial virus; vaccines; virology