Single Hemagglutinin Mutations That Alter both Antigenicity and Receptor Binding Avidity Influence Influenza Virus Antigenic Clustering
Single Hemagglutinin Mutations That Alter both Antigenicity and Receptor Binding Avidity Influence Influenza Virus Antigenic Clustering
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DOI：
10.1128/jvi.01023-13
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Hensley, Scott E.
中科院分区：
文献类型：
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作者：
Li, Yang;Bostick, David L.;Hensley, Scott E.
血凝抑制 (HAI) 测定是用于鉴定抗原性新型流感病毒株的主要测量方法。 HAI 测定测量防止病毒与红细胞结合所需的参考血清量。在解释这些测定时，通常不考虑病毒株的受体结合亲和力。在这里，我们创建了人类 H3N2 病毒的抗原图谱，通过计算解释了病毒受体结合亲和力的变化。这些新的抗原图谱与仅基于 HAI 测量的传统抗原图谱有质的不同。我们通过实验重点关注与 1992 年至 1995 年间发生的单个 N145K 血凝素 (HA) 取代相关的抗原簇。反向遗传学实验表明，N145K HA 突变增加了病毒受体结合亲和力。酶联免疫吸附测定 (ELISA) 显示 N145K HA 突变不会阻止抗体结合；相反，拥有这种突变的病毒在 HAI 检测中只需更有效地附着在细胞上即可逃避抗血清。出乎意料的是，我们发现了N145K HA突变的不对称抗原效应。一旦 H3N2 病毒获得 K145，涉及氨基酸 145 的表位就成为抗原优势。针对具有 K145 的 H3N2 菌株产生的抗血清对具有 N145 的 H3N2 菌株的反应性降低。因此，HA 的个体突变可以通过改变受体结合亲合力和改变抗体反应的优势来影响菌株的抗原分组。我们的结果表明，在进行抗原分析时，考虑病毒受体结合亲和力的变化非常重要，以便识别流感病毒变体之间真正的抗原差异。
The hemagglutination inhibition (HAI) assay is the primary measurement used for identifying antigenically novel influenza virus strains. HAI assays measure the amount of reference sera required to prevent virus binding to red blood cells. Receptor binding avidities of viral strains are not usually taken into account when interpreting these assays. Here, we created antigenic maps of human H3N2 viruses that computationally account for variation in viral receptor binding avidities. These new antigenic maps differ qualitatively from conventional antigenic maps based on HAI measurements alone. We experimentally focused on an antigenic cluster associated with a single N145K hemagglutinin (HA) substitution that occurred between 1992 and 1995. Reverse-genetics experiments demonstrated that the N145K HA mutation increases viral receptor binding avidity. Enzyme-linked immunosorbent assays (ELISA) revealed that the N145K HA mutation does not prevent antibody binding; rather, viruses possessing this mutation escape antisera in HAI assays simply by attaching to cells more efficiently. Unexpectedly, we found an asymmetric antigenic effect of the N145K HA mutation. Once H3N2 viruses acquired K145, an epitope involving amino acid 145 became antigenically dominant. Antisera raised against an H3N2 strain possessing K145 had reduced reactivity to H3N2 strains possessing N145. Thus, individual mutations in HA can influence antigenic groupings of strains by altering receptor binding avidity and by changing the dominance of antibody responses. Our results indicate that it will be important to account for variation in viral receptor binding avidity when performing antigenic analyses in order to identify genuine antigenic differences among influenza virus variants.