title: Viral load drives disease in humans experimentally infected with respiratory syncytial virus.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties in performing pediatric proof-of-concept studies and the prevailing concept that the disease is immune-mediated rather than being driven by viral load.
  
  
  OBJECTIVE
  The development of a human experimental wild-type RSV infection model to address these challenges.
  
  
  METHODS
  Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3.0-5.4 log plaque-forming units/person) of wild-type RSV-A intranasally.
  
  
  RESULTS
  Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity, and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by real-time polymerase chain reaction) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6 and IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical examination, and amount of nasal mucus).
  
  
  CONCLUSIONS
  Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates the development of future RSV therapeutics.
authors.affiliation: Department of Pediatrics, University of Tennessee College of Medicine, Memphis, USA. jdevincenzo@uthsc.edu
authors.forename: John P
authors.initials: JP
authors.lastname: DeVincenzo
authors.forename: Tom
authors.initials: T
authors.lastname: Wilkinson
authors.forename: Akshay
authors.initials: A
authors.lastname: Vaishnaw
authors.forename: Jeff
authors.initials: J
authors.lastname: Cehelsky
authors.forename: Rachel
authors.initials: R
authors.lastname: Meyers
authors.forename: Saraswathy
authors.initials: S
authors.lastname: Nochur
authors.forename: Lisa
authors.initials: L
authors.lastname: Harrison
authors.forename: Patricia
authors.initials: P
authors.lastname: Meeking
authors.forename: Alex
authors.initials: A
authors.lastname: Mann
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moane
authors.forename: John
authors.initials: J
authors.lastname: Oxford
authors.forename: Rajat
authors.initials: R
authors.lastname: Pareek
authors.forename: Ryves
authors.initials: R
authors.lastname: Moore
authors.forename: Ed
authors.initials: E
authors.lastname: Walsh
authors.forename: Robert
authors.initials: R
authors.lastname: Studholme
authors.forename: Preston
authors.initials: P
authors.lastname: Dorsett
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.forename: Robert
authors.initials: R
authors.lastname: Lambkin-Williams
mesh_terms: D000293:Adolescent; D000328:Adult; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D017817:Nasal Lavage Fluid / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000209:etiology / Q000821:virology*; D012136:Respiratory Syncytial Viruses / Q000254:growth & development / Q000472:pathogenicity*; D019562:Viral Load; D010948:Viral Plaque Assay; D055815:Young Adult
chemical_list: D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6