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4
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Morbidity and mortality associated with nosocomial transmission of oseltamivir-resistant influenza A(H1N1) virus.与耐奥司他韦甲型H1N1流感病毒的医院内传播相关的发病率和死亡率。
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用唾液酸酶融合蛋白 DAS181 选择的流感病毒突变体的表型和基因型特征。

Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181.

机构信息

NexBio, Inc., San Diego, CA, USA.

出版信息

J Antimicrob Chemother. 2011 Jan;66(1):15-28. doi: 10.1093/jac/dkq387. Epub 2010 Nov 21.

DOI:10.1093/jac/dkq387
PMID:21097900
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3001847/
Abstract

BACKGROUND

influenza viruses (IFVs) frequently achieve resistance to antiviral drugs, necessitating the development of compounds with novel mechanisms of action. DAS181 (Fludase), a sialidase fusion protein, may have a reduced potential for generating drug resistance due to its novel host-targeting mechanism of action.

METHODS

IFV strains B/Maryland/1/59 and A/Victoria/3/75 (H3N2) were subjected to >30 passages under increasing selective pressure with DAS181. The DAS181-selected IFV isolates were characterized in vitro and in mice.

RESULTS

despite extensive passaging, DAS181-selected viruses exhibited a very low level of resistance to DAS181, which ranged between 3- and 18-fold increase in EC(50). DAS181-selected viruses displayed an attenuated phenotype in vitro, as exhibited by slower growth, smaller plaque size and increased particle to pfu ratios relative to wild-type virus. Further, the DAS181 resistance phenotype was unstable and was substantially reversed over time upon DAS181 withdrawal. In mice, the DAS181-selected viruses exhibited no greater virulence than their wild-type counterparts. Genotypic and phenotypic analysis of DAS181-selected viruses revealed mutations in the haemagglutinin (HA) and neuraminidase (NA) molecules and also changes in HA and NA function.

CONCLUSIONS

results indicate that resistance to DAS181 is minimal and unstable. The DAS181-selected IFV isolates exhibit reduced fitness in vitro, likely due to altered HA and NA functions.

摘要

背景

流感病毒（IFV）经常对抗病毒药物产生耐药性，因此需要开发具有新型作用机制的化合物。唾液酸酶融合蛋白 DAS181（Fludase）由于其新型的宿主靶向作用机制，可能具有降低产生耐药性的潜力。

方法

将 IFV 株 B/Maryland/1/59 和 A/Victoria/3/75（H3N2）在含有 DAS181 的递增选择压力下进行>30 次传代。对 DAS181 选择的 IFV 分离株进行了体外和体内的鉴定。

结果

尽管进行了广泛的传代，但 DAS181 选择的病毒对 DAS181 的耐药性非常低，EC（50）的耐药性增加了 3-18 倍。DAS181 选择的病毒在体外表现出较弱的表型，其生长速度较慢、斑块尺寸较小且颗粒与空斑形成单位（pfu）的比值增加，与野生型病毒相比。此外，DAS181 耐药表型不稳定，随着时间的推移，在停止使用 DAS181 后，耐药表型会大大逆转。在小鼠中，DAS181 选择的病毒的毒力与野生型病毒相比没有增加。DAS181 选择的病毒的基因型和表型分析显示，血凝素（HA）和神经氨酸酶（NA）分子发生了突变，并且 HA 和 NA 功能也发生了变化。

结论

结果表明，DAS181 的耐药性很小且不稳定。DAS181 选择的 IFV 分离株在体外的适应性降低，可能是由于 HA 和 NA 功能改变所致。