Immunogenetic mechanisms driving norovirus GII.4 antigenic variation.
Immunogenetic mechanisms driving norovirus GII.4 antigenic variation.
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DOI：
10.1371/journal.ppat.1002705
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Baric RS
中科院分区：
文献类型：
--
作者：
Lindesmith LC;Beltramello M;Donaldson EF;Corti D;Swanstrom J;Debbink K;Lanzavecchia A;Baric RS
诺如病毒是世界范围内流行性肠胃炎的主要原因，其中GII.4菌株占80%的感染。GII.4菌株的主要衣壳蛋白正在迅速进化，导致新的流行菌株具有改变的抗原潜力。为了测试抗原漂移是否有助于GII.4的持久性，我们对人类记忆B细胞进行了永生化处理，并鉴定了所产生的人类单克隆抗体（mab）对一组时间顺序的GII.4病毒样颗粒（VLPs）的反应性。反映了志愿者、人类抗gii的复杂暴露史。4个单抗分为三种VLP反应模式；祖先（1987-1997），当代（2004-2009）和广义（1987-2009）。通过EIA和封锁，NVB 114仅对最早的GII.4 VLPs起反应。nvb97特异性结合并阻断当代GII.4 VLPs，而nbv111和43.9仅与GII.4.2006 Minerva菌株的变体反应并阻断。3个单抗具有广泛的GII.4反应性。其中，NVB 37.10和61.3也通过EIA检测到其他基因组II vllp，但没有阻断任何VLP与碳水化合物配体的相互作用。通过vlp -碳水化合物阻断试验测定，NVB 71.4交叉中和了时序GII.4 VLPs。利用设计用于改变预测抗原表位的突变型VLPs，绘制了两个进化的、gii .4特异性的阻断表位。结合NVB 114、111和43.9 mab需要氨基酸294-298和368-372。氨基酸393-395是结合NVB 97所必需的，支持抗体阻断逃逸与碳水化合物结合变化之间的早期相关性。这些数据为VLP疫苗设计提供了信息，为扩大嵌合VLP疫苗的交叉阻断潜力提供了策略，并确定了一种具有广泛中和治疗潜力的抗体，用于治疗人类疾病。此外，这些数据支持这样的假设，即GII.4诺如病毒的进化在很大程度上受到中和表位的抗原变异的影响，因此，抗体驱动的受体转换；因此，保护性群体免疫是诺如病毒分子进化的驱动力。诺如病毒是世界范围内流行性肠胃炎的主要原因，其中GII.4菌株占80%的感染。GII.4菌株的主要衣壳蛋白正在迅速进化，导致抗原位点发生改变的新流行菌株。为了确定这些位点，我们通过永生化记忆B细胞和表征抗体反应性和碳水化合物阻断反应，在大约20年的时间顺序的GII.4病毒样颗粒（VLPs）中制备了第一个针对GII.4诺如病毒的人单克隆抗体（Hu mab）。反映了患者的复杂暴露史，人类抗gii。4个单抗分为三种VLP反应模式：广泛（1987-2009），当代（2004-2009）和祖先（1987-2002）。我们还确定了几个确定的表位的位置，这些表位随着时间的推移而进化并驱动抗原变化。我们的数据表明，针对这些位点的抗体阻断了碳水化合物的结合，并可能选择新菌株的出现，这些菌株逃避群体免疫并识别进入的独特碳水化合物，从而导致易感人群中新的疾病爆发。重要的是，这些研究为诺如病毒病的广泛活性疫苗和免疫疗法的合理设计提供了重要信息。
Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution. Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic sites. To define these sites we prepared the first human monoclonal antibodies (Hu mAbs) against GII.4 noroviruses by immortalizing memory B cells and characterizing antibody reactivity and carbohydrate blockade responses across a ∼20 year panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the patient, human anti-GII.4 mAbs grouped into three VLP reactivity patterns: broad (1987–2009), contemporary (2004–2009), and ancestral (1987–2002). We also identified the location of several defined epitopes which evolve over time and drive antigenic change. Our data indicate that antibodies targeting these sites block carbohydrate binding and likely select for the emergence of new strains that escape herd immunity and recognize unique carbohydrates for entry, resulting in new outbreaks of disease in vulnerable human populations. Importantly, these studies critically inform the rational design of broadly active vaccines and immunotherapeutics for the treatment of norovirus disease.
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DOI：
10.1056/nejmoa1101245
发表时间：
2011-12-08
期刊：
The New England journal of medicine
影响因子：
--
作者：
Atmar RL;Bernstein DI;Harro CD;Al-Ibrahim MS;Chen WH;Ferreira J;Estes MK;Graham DY;Opekun AR;Richardson C;Mendelman PM
通讯作者：
Mendelman PM
影响因子：
--
作者：
Czako, Rita;Atmar, Robert L.;Estes, Mary K.
通讯作者：
Estes, Mary K.
影响因子：
5.4
作者：
de Rougemont, A.;Ruvoen-Clouet, N.;Belliot, G.
通讯作者：
Belliot, G.
影响因子：
14.9
作者：
Chenna, R;Sugawara, H;Thompson, JD
通讯作者：
Thompson, JD
影响因子：
5.4
作者：
Cao, Sheng;Lou, Zhiyong;Rao, Zihe
通讯作者：
Rao, Zihe