Assessing the Viral Fitness of Oseltamivir-Resistant Influenza Viruses in Ferrets, Using a Competitive-Mixtures Model
Assessing the Viral Fitness of Oseltamivir-Resistant Influenza Viruses in Ferrets, Using a Competitive-Mixtures Model
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DOI：
10.1128/jvi.00373-10
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发表时间：
2010-09-15
影响因子：
5.4
通讯作者：
Barr, Ian G.
中科院分区：
文献类型：
--
作者：
Hurt, Aeron C.;Nor'e, Siti Sarah;Barr, Ian G.
为了确定与敏感的野生型病毒相比，奥司他韦耐药株的相对适合性，我们将数学建模和统计技术与一种新的体内“竞争混合物”实验模型相结合。在相同的传染性滴度下，雪貂被纯种群(100%敏感野生型或100%奥司他韦耐药突变病毒)或野生型与奥司他韦抗性流感病毒(80%：20%、50%：50%和20%：80%)混合感染，并在宿主内和宿主间接触模型中监测这两种病毒相对比例的变化。用抗奥司他韦的R292K突变体A(H3N2)病毒和对奥司他韦敏感的野生型病毒混合感染雪貂的结果表明，R292K突变病毒在人工感染的供体雪貂中迅速超过R292野生型病毒的生长，并且不会传播给任何受体雪貂。竞争混合模型也被用来研究季节性A(H1N1)奥司他韦耐药突变株H274Y的适合性，结果表明，在感染的雪貂体内，H274Y突变株的生长略高于野生型，但在雪貂之间表现出同等的传播力。与仅用纯病毒群感染雪貂的更传统方法相比，这种新颖的活体实验方法和伴随的数学分析提供了对两种不同流感病毒株在宿主内部和宿主之间的相对适合度的更大洞察。我们的统计推断对于开发下一代奥司他韦耐药流感在人类人群中出现和传播的数学模型至关重要。
To determine the relative fitness of oseltamivir-resistant strains compared to susceptible wild-type viruses, we combined mathematical modeling and statistical techniques with a novel in vivo "competitive-mixtures" experimental model. Ferrets were coinfected with either pure populations (100% susceptible wild-type or 100% oseltamivir-resistant mutant virus) or mixed populations of wild-type and oseltamivir-resistant influenza viruses (80%:20%, 50%:50%, and 20%:80%) at equivalent infectivity titers, and the changes in the relative proportions of those two viruses were monitored over the course of the infection during within-host and over host-to-host transmission events in a ferret contact model. Coinfection of ferrets with mixtures of an oseltamivir-resistant R292K mutant A(H3N2) virus and a R292 oseltamivir-susceptible wild-type virus demonstrated that the R292K mutant virus was rapidly outgrown by the R292 wild-type virus in artificially infected donor ferrets and did not transmit to any of the recipient ferrets. The competitive-mixtures model was also used to investigate the fitness of the seasonal A(H1N1) oseltamivir-resistant H274Y mutant and showed that within infected ferrets the H274Y mutant virus was marginally outgrown by the wild-type strain but demonstrated equivalent transmissibility between ferrets. This novel in vivo experimental method and accompanying mathematical analysis provide greater insight into the relative fitness, both within the host and between hosts, of two different influenza virus strains compared to more traditional methods that infect ferrets with only pure populations of viruses. Our statistical inferences are essential for the development of the next generation of mathematical models of the emergence and spread of oseltamivir-resistant influenza in human populations.