Human Norovirus Epitope D Plasticity Allows Escape from Antibody Immunity without Loss of Capacity for Binding Cellular Ligands.
Human Norovirus Epitope D Plasticity Allows Escape from Antibody Immunity without Loss of Capacity for Binding Cellular Ligands.
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DOI：
10.1128/jvi.01813-18
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发表时间：
2019-01-15
影响因子：
5.4
通讯作者：
Baric RS
中科院分区：
文献类型：
--
作者：
Lindesmith LC;Brewer-Jensen PD;Mallory ML;Yount B;Collins MH;Debbink K;Graham RL;Baric RS
人类诺如病毒每年引起约20%的急性胃肠炎和约200，000例死亡，主要发生在幼儿中。在过去30年中，大多数流行病和所有大流行性疾病波都是由GII.4型人诺如病毒株引起的。GII.4毒株的衣壳序列随着时间的推移而发生变化，导致病毒的配体和抗体结合特性发生变化。这些菌株的碳水化合物结合口袋不随时间变化。在这里，利用独特的病毒序列，我们研究了GII.4表位D中的残基如何平衡可变抗体结合位点和细胞配体结合稳定结构域的双重作用，表明表位D中的氨基酸变化可以导致抗体结合的丧失而不消除配体结合。表位D的这种灵活性可能通过允许逃避抗体介导的群体免疫和维持细胞配体结合和感染性而有助于GII.4菌株的持久性。出现的人类诺如病毒株引发了一波又一波的疾病大流行。这些新菌株具有改变的配体结合和抗原性特征。对从长期诺如病毒感染的免疫抑制患者中分离的病毒变体的研究表明，初始病毒体内进化发生在与大流行毒株相同的抗原位点。在这里，细胞配体结合和抗原性的两个共循环株分离的患者与长期诺如病毒感染的特点。分离的GII.4病毒与以前的毒株不同，并且在已知的阻断抗体表位上彼此不同。一种菌株在表位D中具有独特的序列，包括在残基394处的插入缺失，对应于对碳水化合物配体的相对亲和力降低。用丙氨酸替换394或恢复当代菌株表位D共有序列STT改善了配体结合相对亲和力。然而，单克隆抗体仅对共有序列获得结合效力的阻断，而不是通过丙氨酸插入。表位D的独特变化的深入研究表明，尽管序列多样性，但配体结合而不是配体结合的抗体阻断得以维持，从而允许从阻断抗体逃逸而不丧失结合细胞配体的能力。重要性人类诺如病毒每年导致约20%的急性胃肠炎和约200，000例死亡，主要发生在幼儿中。在过去30年中，大多数流行病和所有大流行性疾病波都是由GII.4型人诺如病毒株引起的。GII.4毒株的衣壳序列随着时间的推移而发生变化，导致病毒的配体和抗体结合特性发生变化。这些菌株的碳水化合物结合口袋不随时间变化。在这里，利用独特的病毒序列，我们研究了GII.4表位D中的残基如何平衡可变抗体结合位点和细胞配体结合稳定结构域的双重作用，表明表位D中的氨基酸变化可以导致抗体结合的丧失而不消除配体结合。表位D的这种灵活性可能通过允许逃避抗体介导的群体免疫和维持细胞配体结合和感染性而有助于GII.4菌株的持久性。
Human norovirus causes ∼20% of all acute gastroenteritis and ∼200,000 deaths per year, primarily in young children. Most epidemic and all pandemic waves of disease over the past 30 years have been caused by type GII.4 human norovirus strains. The capsid sequence of GII.4 strains is changing over time, resulting in viruses with altered ligand and antibody binding characteristics. The carbohydrate binding pocket of these strains does not vary over time. Here, utilizing unique viral sequences, we study how residues in GII.4 epitope D balance the dual roles of variable antibody binding site and cellular ligand binding stabilization domain, demonstrating that amino acid changes in epitope D can result in loss of antibody binding without ablating ligand binding. This flexibility in epitope D likely contributes to GII.4 strain persistence by both allowing escape from antibody-mediated herd immunity and maintenance of cellular ligand binding and infectivity. Emergent strains of human norovirus seed pandemic waves of disease. These new strains have altered ligand binding and antigenicity characteristics. Study of viral variants isolated from immunosuppressed patients with long-term norovirus infection indicates that initial virus in vivo evolution occurs at the same antigenic sites as in pandemic strains. Here, cellular ligand binding and antigenicity of two cocirculating strains isolated from a patient with long-term norovirus infection were characterized. The isolated GII.4 viruses differed from previous strains and from each other at known blockade antibody epitopes. One strain had a unique sequence in epitope D, including loss of an insertion at residue 394, corresponding to a decreased relative affinity for carbohydrate ligands. Replacement of 394 with alanine or restoration of the contemporary strain epitope D consensus sequence STT improved ligand binding relative affinity. However, monoclonal antibody blockade of binding potency was only gained for the consensus sequence, not by the alanine insertion. In-depth study of unique changes in epitope D indicated that ligand binding, but not antibody blockade of ligand binding, is maintained despite sequence diversity, allowing escape from blockade antibodies without loss of capacity for binding cellular ligands. IMPORTANCE Human norovirus causes ∼20% of all acute gastroenteritis and ∼200,000 deaths per year, primarily in young children. Most epidemic and all pandemic waves of disease over the past 30 years have been caused by type GII.4 human norovirus strains. The capsid sequence of GII.4 strains is changing over time, resulting in viruses with altered ligand and antibody binding characteristics. The carbohydrate binding pocket of these strains does not vary over time. Here, utilizing unique viral sequences, we study how residues in GII.4 epitope D balance the dual roles of variable antibody binding site and cellular ligand binding stabilization domain, demonstrating that amino acid changes in epitope D can result in loss of antibody binding without ablating ligand binding. This flexibility in epitope D likely contributes to GII.4 strain persistence by both allowing escape from antibody-mediated herd immunity and maintenance of cellular ligand binding and infectivity.