Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.
Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.
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DOI：
10.1126/science.abl6251
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发表时间：
2022-01-21
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影响因子：
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许多研究考察了严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)变异株成为优势株后对中和抗体活性的影响。在这里，我们评估病毒进一步进化的后果。我们展示了SARS-CoV-2受体结合域(RBD)可以耐受大量同时抗体逃逸突变的机制，并表明包含多达七个突变的伪型，而不是之前研究的令人担忧的变种中的一个到三个，对疫苗接受者的治疗性抗体和血清的中和更具抵抗力。我们确定了一种与RBD核心结合的抗体，以中和所有测试变体的伪型，但表明RBD可以获得N-连接的多糖来逃避中和。我们的发现预示着，随着SARS-CoV-2适应人类，逃逸变异将继续出现。在新冠肺炎大流行的整个过程中，严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)病毒出现了变异，这些变异增加了传染性或降低了其对现有抗体的易感性。Nabel等人。重点关注病毒表面发现的负责结合和进入宿主细胞的Spike蛋白的突变，并表明该结构在抵抗中和抗体方面表现出可塑性。与伪病毒合作，作者识别了可能导致耐药性的组合突变。他们确定了一种抗体，可以中和具有高度突变尖峰的假型，但也表明SARS-CoV-2可以获得一种多糖来逃避这种中和。如果我们要迅速对令人担忧的新变种做出反应，了解尖峰蛋白抗原谱变化的后果是重要的。-VV当它躲避抗体时，SARS-CoV-2刺突蛋白受体结合域可以获得多个突变和一个糖链。随着严重急性呼吸综合征冠状病毒2(SARS-CoV-2)在自然免疫和疫苗诱导免疫的选择性压力下复制，令人担忧的变种(VOCs)继续出现。通过适应性进化，这些变体获得了与细胞受体血管紧张素转换酶2(ACE2)结合的刺激性蛋白受体结合域(RBD)的突变。尖峰蛋白突变对免疫反应的影响使监测病毒变异变得重要。虽然以前研究的VOCs包含一到三个有时重叠的RBD突变，但正在密切监测包含更多突变的复合变体的可能性。随着世界部分地区继续面临感染浪潮和缓解策略的放松，抗体选择性压力下病毒在人类宿主中的复制继续塑造SARS-CoV-2刺突蛋白的抗原性格局。随着含有复合突变的变种开始出现，在变种成为主导菌株之前，主动检查变种的影响是至关重要的。我们测定了人ACE2与SARS-CoV-2 RBD的复合体的X射线晶体结构，该复合体包含在免疫受损个体持续感染期间出现的六个替换。我们发现，RBD-ACE2界面的结构可塑性允许RBD在保持ACE2亲和力的同时耐受大量突变。我们从免疫受损的宿主衍生序列和VOC中产生了一组带有复合RBD突变(最多7个)的伪型。与之前研究的挥发性有机化合物相比，复合变异体更巧妙地躲避了治疗性抗体中和。在第一次免疫后，但在第二次接种mRNA疫苗之前，我们观察到所有被测试的变异体的疫苗接受者血清中和活性的丧失，尽管严重程度因变异体而异。然而，第二次免疫后的采样显示，可检测到对疫苗接受者血清中所有变异体的中和活性，包括对含有7个复合RBD突变的伪型[表示为受体结合突变体-2(RBM-2)]。为了确定限制中和广度的进化障碍，我们使用SARS-CoV刺突蛋白从一名新冠肺炎恢复期供者身上分离出一种中和抗体。通过结构分析和功能分析，我们发现SARS-CoV-2 RBD获得的N-连结多聚糖对分离的交叉反应抗体和至少一个与类似的、否则高度保守的表位结合的其他抗体具有假型中和抵抗力。因此，在SARS-CoV-2 RBD上获得N-连接的糖链是病毒继续逃避免疫反应的另一种方式。我们发现，RBD-ACE2界面的结构可塑性促进了大量RBD突变的积累，并进一步侵蚀了疫苗接受者的治疗性抗体和血清的活性。此外，在SARS-CoV-2 RBD上获得N-连接的糖链是另一条中和逃逸途径，在病毒抗原漂移期间应该密切监测。结构可塑性适应了RBD ACE2结合部位复合取代的积累，并允许RBD熟练地逃避治疗性抗体。交叉中和抗体结合RBD核心，但RBD残基Asn370(N370)上N-连接的多糖的获得会进一步中和逃逸。氨基酸残基的单字母缩写如下：D，Asp；E，Glu；F，Phe；H，His；K，Lys；L，Leu；N，Asn；P，Pro；Q，Gln；R，Arg；S，Ser；T，Thr；和Y，Tyr。LC，轻链；HC，重链。
Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans. Throughout the course of the COVID-19 pandemic, variants have arisen in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that increase infectivity or reduce its susceptibility to existing antibodies. Nabel et al. focus on mutations in the spike protein, which is found on the viral surface and is responsible for binding and entering host cells, and show that the structure exhibits plasticity in resisting neutralizing antibodies. Working with pseudoviruses, the authors identify combinatorial mutations that might lead to resistance. They identify an antibody that neutralizes a pseudotype with a highly mutated spike, but also show that SARS-CoV-2 can acquire a glycan to escape this neutralization. Understanding the consequences of changes in the antigenic landscape of the spike protein is important if we are to rapidly respond to new variants of concern. —VV As it evades antibodies, the SARS-CoV-2 spike protein receptor-binding domain can acquire multiple mutations and a glycan. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates under selective pressure from natural and vaccine-induced immunity, variants of concern (VOCs) continue to emerge. Through adaptative evolution, these variants acquire mutations in the spike protein receptor binding domain (RBD) that binds the cellular receptor angiotensin-converting enzyme 2 (ACE2). The effects of spike protein mutations on immune responses make it important to monitor viral variants. While previously studied VOCs contain one to three RBD mutations that at times overlap, the potential for composite variants that contain larger numbers of mutations is being closely monitored. As parts of the world continue to face waves of infection and mitigation strategies are relaxed, viral replication in human hosts under antibody selective pressure continues to shape the antigenic landscape of the SARS-CoV-2 spike protein. As variants containing composite mutations begin to emerge, proactive approaches examining the impact of variants before they become dominant strains are critical. We determined the x-ray crystal structure of human ACE2 in complex with a SARS-CoV-2 RBD that contains six substitutions that arose during persistent infection of an immunocompromised individual. We found that structural plasticity at the RBD–ACE2 interface allowed the RBD to tolerate a large number of mutations while retaining ACE2 affinity. We generated a panel of pseudotypes bearing composite RBD mutations (up to seven) from immunocompromised host-derived sequences and VOCs. Composite variants more adeptly evaded therapeutic antibody neutralization than did previously studied VOCs. After first immunization but before the second dose of an mRNA vaccine, we observed a loss in vaccine recipient serum neutralizing activity for all variants tested, although the severity differed depending on the variant. However, sampling after the second immunization revealed detectable neutralizing activity against all variants in the serum of vaccine recipients, including against a pseudotype that contains seven composite RBD mutations [denoted receptor binding mutant-2 (RBM-2)]. To identify evolutionary barriers that restrict neutralization breadth, we used the SARS-CoV spike protein to isolate a neutralizing antibody from a COVID-19 convalescent donor. Through structural analysis and functional assays, we show that N-linked glycan acquisition by the SARS-CoV-2 RBD confers pseudotype resistance to neutralization by the isolated cross-reactive antibody and at least one other antibody that binds a similar, otherwise highly conserved epitope. Therefore, acquisition of an N-linked glycan on the SARS-CoV-2 RBD is an additional means through which the virus could continue to evade immune responses. We find that accumulation of large numbers of RBD mutations is facilitated by structural plasticity at the RBD–ACE2 interface and further erodes the activity of therapeutic antibodies and serum from vaccine recipients. Furthermore, acquisition of an N-linked glycan on the SARS-CoV-2 RBD is an additional neutralization escape pathway that should be closely monitored during viral antigenic drift. Structural plasticity accommodates the accumulation of composite substitutions in the RBD ACE2 binding site and allows the RBD to adeptly escape therapeutic antibodies. Cross-neutralizing antibodies bind the RBD core, but acquisition of an N-linked glycan at RBD residue Asn370 (N370) drives further neutralization escape. Single-letter abbreviations for the amino acid residues are as follows: D, Asp; E, Glu; F, Phe; H, His; K, Lys; L, Leu; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; and Y, Tyr. LC, light chain; HC, heavy chain.
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影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
17.1
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Jones BE;Brown-Augsburger PL;Corbett KS;Westendorf K;Davies J;Cujec TP;Wiethoff CM;Blackbourne JL;Heinz BA;Foster D;Higgs RE;Balasubramaniam D;Wang L;Zhang Y;Yang ES;Bidshahri R;Kraft L;Hwang Y;Žentelis S;Jepson KR;Goya R;Smith MA;Collins DW;Hinshaw SJ;Tycho SA;Pellacani D;Xiang P;Muthuraman K;Sobhanifar S;Piper MH;Triana FJ;Hendle J;Pustilnik A;Adams AC;Berens SJ;Baric RS;Martinez DR;Cross RW;Geisbert TW;Borisevich V;Abiona O;Belli HM;de Vries M;Mohamed A;Dittmann M;Samanovic MI;Mulligan MJ;Goldsmith JA;Hsieh CL;Johnson NV;Wrapp D;McLellan JS;Barnhart BC;Graham BS;Mascola JR;Hansen CL;Falconer E
通讯作者：
Falconer E
DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group
DOI：
10.1126/science.1187816
发表时间：
2010-06-04
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Bloom JD;Gong LI;Baltimore D
通讯作者：
Baltimore D
影响因子：
64.5
作者：
Kang L;He G;Sharp AK;Wang X;Brown AM;Michalak P;Weger-Lucarelli J
通讯作者：
Weger-Lucarelli J