title: Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection.
abstract: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. Effective treatment for RSV infection is a significant unmet medical need. While new RSV therapeutics are now in development, there are very few animal models that mimic the pathogenesis of human RSV, making it difficult to evaluate new disease interventions. Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory infection that is similar to human RSV infection, providing a relevant model for testing novel therapeutic agents. In this model, viral load is readily detected in nasal secretions by quantitative real-time PCR (qRT-PCR), and cumulative symptom scoring together with histopathology evaluations of infected tissue allow for the assessment of disease severity. The bovine RSV model was used to evaluate the antiviral activity of an RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in two randomized, blind, placebo-controlled studies in bRSV-infected calves. Intravenous administration of GS1 at 4 mg/kg of body weight/day for 7 days starting 24 h or 72 h postinoculation provided clear therapeutic benefit by reducing the viral load, disease symptom score, respiration rate, and lung pathology associated with bRSV infection. These data support the use of the bovine RSV model for evaluation of experimental therapeutics for treatment of RSV.
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Shao
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Mackman
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Perron
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Sandy A
authors.initials: SA
authors.lastname: Lewis
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Eisenberg
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Carey
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Strickley
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Chien
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Anderson
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: McEligot
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Behrens
authors.affiliation: Department of Pathology, Microbiology & Immunology, School of Veterinary Medicine, University of California, Davis, Davis, California, USA ljgershwin@ucdavis.edu.
authors.forename: Laurel J
authors.initials: LJ
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001988:Bronchiolitis / Q000188:drug therapy / Q000821:virology; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D002460:Cell Line; D002462:Cell Membrane / Q000473:pathology / Q000821:virology; D004311:Double-Blind Method; D006801:Humans; D007191:Indazoles; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000473:pathology; D018112:Respiratory Syncytial Virus, Bovine / Q000187:drug effects*; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D019562:Viral Load / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007191:Indazoles; D011720:Pyrazoles; D013449:Sulfonamides; C000591241:presatovir