BACKGROUND Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir. METHODS NAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu- 3. RESULTS We found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus. CONCLUSIONS Although the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.

中文翻译：

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与使用神经氨酸酶抑制剂相关的甲型流感病毒血凝素突变与抗流感抗体的抑制作用降低有关。

背景技术疫苗接种和神经氨酸酶抑制剂（NAIs）的使用目前是抵抗季节性流感的前线。流感疫苗和抗病毒药物（例如NAI）的活性可能会受到流感血凝素（HA）蛋白突变的影响。在非临床NAI抗性选择实验以及NAI治疗或监测研究的临床标本中，已经鉴定出许多HA替代物。这些突变在FDA批准的NAI的处方信息（包装插页）中列出，包括oseltamivir，zanamivir和peramivir。方法将NAI治疗产生的H1 HA突变定位到H1N1 HA1三聚体晶体结构上，并将其大多数定位在预测对抗流感免疫至关重要的HA抗原位点上。产生带有HA V152I，G155E，S162 N，S183P和D222G突变的重组A /加利福尼亚/ 04/09（H1N1）样病毒。然后，我们评估了这些突变对重组​​病毒在人呼吸道上皮细胞系Calu-3中的免疫反应性和复制潜能的影响。结果我们发现，与相比，G155E和D222G突变显着提高了病毒效价〜13倍。野生型病毒。与携带野生型病毒的G155E或D222G突变株相比，针对大流行A（H1N1）pdm09病毒的山羊和雪貂抗血清，单克隆抗体和人血清样品的血凝和微中和活性比携带G155E或D222G的突变株低约100倍。结论尽管NAI治疗期间HA突变出现的机制尚不确定，