Viral Load Drives Disease in Humans Experimentally Infected with Respiratory Syncytial Virus

Department of Pediatrics, University of Tennessee College of Medicine, Memphis, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 11/2010; 182(10):1305-14. DOI: 10.1164/rccm.201002-0221OC
Source: PubMed


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.
The development of a human experimental wild-type RSV infection model to address these challenges.
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.
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).
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.

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Available from: Tom M Wilkinson, Apr 03, 2014
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    • "The virus was manufactured under GMP conditions as previously described (DeVincenzo et al., 2010). Challenge virus was prepared in accordance with standard Retroscreen (hVIVO) procedures and administered intra-nasally. "
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    • "Sucrose was added to 8% and the virus stock was frozen at −80 °C and titered for infectivity on HEp-2 cells. RSV M37 is a wild type RSV-A first isolated from infected humans and used in human clinical studies [25]. The amount and dose of virus used in these studies is similar to those from our previous work with RSV A2 strain [10]. "
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    • "RSV is a major cause of morbidity and mortality globally, particularly in infants, for which there is currently no effective vaccination or treatment available. In experimentally induced RSV infection in adult volunteers, early high viral titres have been found to correlate with severity of inflammatory disease manifestations [25]. In addition, more severe disease in infants is associated with high viral titres in early stages of naturally-occurring RSV bronchiolitis [26]. "
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