Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility
Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility
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DOI：
10.1128/aac.49.10.4075-4084.2005
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发表时间：
2005-10-01
影响因子：
4.9
通讯作者：
Govorkova, EA
中科院分区：
文献类型：
--
作者：
Yen, HL;Herlocher, LM;Govorkova, EA
与 NA 抑制剂 (NAI) 抗性相关的流感病毒神经氨酸酶 (NA) 保守残基的突变会降低 NA 的唾液酸酶活性和/或稳定性，从而损害病毒适应性。事实上，临床上衍生的具有不同 NA 突变的 NAI 抗性变异体在雪貂中表现出不同的传播性。需要对具有同质遗传背景的突变病毒进行分子表征，以确定保守 NA 残基处单一突变的影响。我们通过反向遗传学在 A/Wuhan/359/95 (H3N2) 流感病毒背景中生成了含有野生型 NA（RG WT 病毒）或 NA 残基 119（RG E119V-NA 病毒）或 292（RG R292K-NA 病毒）单个氨基酸变化的重组病毒。两种突变体均表现出对羧酸奥司他韦的敏感性降低，并且RG R292K-NA病毒表现出对扎那米韦的交叉耐药性。我们还观察到两个突变体在 NA 酶活性和热稳定性方面的差异。 R292K突变比E119V突变导致唾液酸酶活性和热稳定性更大程度的降低。 R292K突变引起的NA缺陷与生长和传播能力受损相关，而RG E119V-NA病毒的生长和传播能力与RG WT病毒相当。我们的结果表明，NAI 抗性流感病毒变种在适应性和传播性方面可能存在很大差异，具体取决于 NA 功能丧失的不同程度。
Mutations of the conserved residues of influenza virus neuraminidase (NA) that are associated with NA inhibitor (NAI) resistance decrease the sialidase activity and/or stability of the NA, thus compromising viral fitness. In fact, clinically derived NAI-resistant variants with different NA mutations have shown different transmissibilities in ferrets. Molecular characterization of mutant viruses that have a homogeneous genetic background is required to determine the effect of single mutations at conserved NA residues. We generated recombinant viruses containing either the wild-type NA (RG WT virus) or a single amino acid change at NA residue 119 (RG E119V-NA virus) or 292 (RG R292K-NA virus) in the A/Wuhan/359/95 (H3N2) influenza virus background by reverse genetics. Both mutants showed decreased sensitivity to oseltamivir carboxylate, and the RG R292K-NA virus showed cross-resistance to zanamivir. We also observed differences between the two mutants in NA enzymatic activity and thermostability. The R292K mutation caused greater reduction of sialidase activity and thermostability than the E119V mutation. The NA defect caused by the R292K mutation was associated with compromised growth and transmissibility, whereas the growth and transmissibility of the RG E119V-NA virus were comparable to those of RG WT virus. Our results suggest that NAI-resistant influenza virus variants may differ substantially in fitness and transmissibility, depending on different levels of NA functional loss.