Structural differences among hemagglutinins of influenza A virus subtypes are reflected in their antigenic architecture: Analysis of H9 escape mutants
Structural differences among hemagglutinins of influenza A virus subtypes are reflected in their antigenic architecture: Analysis of H9 escape mutants
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DOI：
10.1128/jvi.78.1.240-249.2004
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发表时间：
2004-01-01
影响因子：
5.4
通讯作者：
Webster, RG
中科院分区：
文献类型：
--
作者：
Kaverin, NV;Rudneva, IA;Webster, RG
我们使用一组针对 H9 血凝素的单克隆抗体来选择 18 种小鼠适应的甲型流感/猪/香港/9/98 (H9N2) 病毒的逃逸突变体。突变体与抗体的交叉反应和血凝素基因的测序揭示了两个最小重叠的表位。我们将氨基酸变化映射到最近报道的 A/Swine/Hong Kong/9/98 血凝素三维结构的两个区域。 H9 血凝素中抗原相关氨基酸位置的分组与在 H3 和 H5 血凝素中观察到的模式不同。 H3血凝素B位点的几个位置分布在H9血凝素的两个位点上。与迄今为止分析的任何亚型不同，H9 血凝素不包含与 H3 血凝素中的 A 位点相对应的抗原位点。位置 145 和 193（H3 编号）在 H3 血凝素中分别属于位点 A 和 B，在 H9 血凝素中位于一个位点内。这一发现与H9分子三维结构的特殊性相一致，即H9血凝素中不存在形成H3中的A位点和H5血凝素中的等效位点的侧环。分析的逃逸突变体表现出表型变异，包括对小鼠的毒力降低以及对唾液酸底物的亲和力变化。我们的结果证明了三维结构的亚型间差异与抗原区域分布的亚型差异之间的相关性。我们的研究结果还表明，抗体选择的突变的共变和多效性可能在 H9 流感病毒的进化中很重要，而 H9 流感病毒可能是未来大流行的病原体。
We used a panel of monoclonal antibodies to H9 hemagglutinin to select 18 escape mutants of mouse-adapted influenza A/Swine/Hong Kong/9/98 (H9N2) virus. Cross-reactions of the mutants with the antibodies and the sequencing of hemagglutinin genes revealed two minimally overlapping epitopes. We mapped the amino acid changes to two areas of the recently reported three-dimensional structure of A/Swine/Hong Kong/9/98 hemagglutinin. The grouping of the antigenically relevant amino acid positions in H9 hemagglutinin differs from the pattern observed in H3 and H5 hemagglutinins. Several positions in site B of H3 hemagglutinin are distributed in two sites of H9 hemagglutinin. Unlike any subtype analyzed so far, H9 hemagglutinin does not contain an antigenic site corresponding to site A in H3 hemagglutinin. Positions 145 and 193 (H3 numbering), which in H3 hemagglutinin belong to sites A and B, respectively, are within one site in H9 hemagglutinin. This finding is consistent with the peculiarity of the three-dimensional structure of the H9 molecule, that is, the absence from H9 hemagglutinin of the lateral loop that forms site A in H3 and the equivalent site in H5 hemagglutinins. The escape mutants analyzed displayed phenotypic variations, including decreased virulence for mice and changes in affinity for sialyl substrates. Our results demonstrate a correlation between intersubtype differences in three-dimensional structure and variations among subtypes in the distribution of antigenic areas. Our findings also suggest that covariation and pleiotropic effects of antibody-selected mutations may be important in the evolution of H9 influenza virus, a possible causative agent of a future pandemic.