Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir
Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir
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DOI：
10.1086/318537
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发表时间：
2001-02-15
影响因子：
6.4
通讯作者：
Hayden, FG
中科院分区：
文献类型：
--
作者：
Gubareva, LV;Kaiser, L;Hayden, FG
实验性感染甲型/德克萨斯/36/91 (H1N1) 流感病毒并接受神经氨酸酶 (NA) 抑制剂奥司他韦治疗的志愿者被监测是否出现耐药变异。在从 54 名药物接受者身上回收的最后一天分离株中，通过 NA 抑制测定检测到了 54 种耐药病毒中的 2 种（4%）。他们在北美赛区替换了 His274Tyr。安慰剂组中检测到的血凝素 (HA) 变异体与卵适应接种病毒的不同之处在于残基 137、225 或两者处的氨基酸取代。这些变体对含有 Neu5Ac(α2-6)Gal 的受体（人类呼吸道上皮的特征）的亲和力高于对含有 Neu5Ac(α2-3)Gal 的受体（鸡蛋尿囊膜的典型特征）的亲和力。尽管在人类中似乎对奥司他韦更敏感，但对 Neu5Ac(alpha2-6)Gal 受体亲和力增加的变体的敏感性低于 Madin-Darby 犬肾细胞中的 Neu5Ac(alpha2-3)Gal 结合变体。因此，HA 对受体的亲和力是流感病毒对 NA 抑制剂敏感的一个基本特征，无论是在细胞培养物还是在人类中。
Volunteers experimentally infected with influenza A/Texas/36/91 (H1N1) virus and treated with the neuraminidase (NA) inhibitor oseltamivir were monitored for the emergence of drug-resistant variants. Two (4%) of 54 resistant viruses were detected by NA inhibition assay among last-day isolates recovered from 54 drug recipients. They bore a substitution His274Tyr in the NA. Hemagglutinin (HA) variants detected in the placebo group differed from the egg-adapted inoculum virus by virtue of amino acid substitutions at residues 137, 225, or both. These variants had a higher affinity for Neu5Ac(alpha2-6)Gal-containing receptors, which are characteristic of human respiratory epithelium, than for Neu5Ac(alpha2-3)Gal-containing receptors, which are typical of chicken egg allantoic membrane. Although appearing to be more sensitive to oseltamivir in humans, the variants with increased affinity for Neu5Ac(alpha2-6)Gal receptors were less sensitive than the Neu5Ac(alpha2-3)Gal-binding variants in Madin-Darby canine kidney cells. Thus, HA affinity for receptors is an essential feature of influenza virus susceptibility to NA inhibitors, both in cell culture and in humans.