Viral Load Drives Disease in Humans Experimentally Infected with Respiratory Syncytial Virus
Viral Load Drives Disease in Humans Experimentally Infected with Respiratory Syncytial Virus
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DOI：
10.1164/rccm.201002-0221oc
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发表时间：
2010-11-15
影响因子：
24.7
通讯作者：
Lambkin-Williams, Robert
中科院分区：
文献类型：
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作者：
DeVincenzo, John P.;Wilkinson, Tom;Lambkin-Williams, Robert
理由。呼吸道合胞病毒（RSV）是儿童下呼吸道感染的主要原因，然而，缺乏可行的治疗方法两个主要的挑战，我们停止了抗病毒药物的开发，在进行儿科概念研究的证明中存在伦理困难，以及流行的概念，即疾病是免疫介导的，而不是由病毒载量驱动的目的开发人类实验野生型RSV感染模型来解决这些挑战。健康志愿者（n = 35），在5个队列中，（3 0-5 4 log空斑形成单位/人）的鼻内野生型RSV A的测量和主要结果总体而言，77%的志愿者持续地排出病毒感染率、病毒载量、疾病严重程度，和安全性相似，并且与接受的RSV数量无关。症状在最初病毒检测时开始，当病毒载量达到峰值时，70例患者达到峰值，（通过真实的时间聚合酶链反应测量）缓慢下降病毒载量与鼻内促炎细胞因子浓度显著相关（IL-6和IL-8）病毒载量增加与多种不同疾病测量值的增加一致（症状、体格检查和鼻粘液量）结论病毒载量似乎驱动RSV感染的人类的疾病表现。观察到的平行病毒和疾病动力学支持RSV抗病毒药物的潜在临床益处。
Rationale. Respiratory,syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking Two major challenges h we 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 loadObjectives The development of a human experimental wild type RSV infection model to address these challengesMethods Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3 0-5 4 log plaque forming units/person) of wild type RSV A intranasallyMeasurements and Main 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 seventy 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