Gubareva L V, Kaiser L, Matrosovich M N, Soo-Hoo Y, Hayden F G
Department of Internal Medicine, Division of Epidemiology and Virology, University of Virginia, PO Box 473, Charlottesville, VA 22908, USA.
J Infect Dis. 2001 Feb 15;183(4):523-31. doi: 10.1086/318537. Epub 2001 Jan 11.
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.
对感染了甲型/得克萨斯/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进行监测，以观察耐药变异株的出现情况。在从54名接受药物治疗者中回收的末次分离株中，通过NA抑制试验检测到54株耐药病毒中有2株（4%）。它们的NA中存在His274Tyr替代。在安慰剂组中检测到的血凝素（HA）变异株与鸡胚适应接种病毒不同，其137位、225位或这两个位点的氨基酸发生了替代。这些变异株对含Neu5Ac（α2-6）Gal的受体（人呼吸道上皮细胞的特征性受体）的亲和力高于对含Neu5Ac（α2-3）Gal的受体（鸡胚尿囊膜的典型受体）的亲和力。尽管在人类中似乎对奥司他韦更敏感，但对Neu5Ac（α2-6）Gal受体亲和力增加的变异株在马-达二氏犬肾细胞中比结合Neu5Ac（α2-3）Gal的变异株敏感性更低。因此，HA对受体的亲和力是流感病毒在细胞培养和人类中对NA抑制剂敏感性的一个重要特征。
