Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization.
Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization.
复制标题
DOI：
10.1016/j.celrep.2017.07.077
复制
发表时间：
2017-08-22
期刊：
影响因子：
8.8
通讯作者：
Sanders RW
中科院分区：
文献类型：
--
作者：
Torrents de la Peña A;Julien JP;de Taeye SW;Garces F;Guttman M;Ozorowski G;Pritchard LK;Behrens AJ;Go EP;Burger JA;Schermer EE;Sliepen K;Ketas TJ;Pugach P;Yasmeen A;Cottrell CA;Torres JL;Vavourakis CD;van Gils MJ;LaBranche C;Montefiori DC;Desaire H;Crispin M;Klasse PJ;Lee KK;Moore JP;Ward AB;Wilson IA;Sanders RW
HIV-1包膜糖蛋白（Env）三聚体的天然样重组形式的产生需要克服复合物的天然柔性和不稳定性。工程改造的BG 505 SOSIP.664三聚体模拟天然Env的结构和抗原性。在这里，我们描述了糖蛋白（gp）120和gp 41亚基的BG 505和其他基因型的SOSIP三聚体之间的新的二硫键的引入如何提高其稳定性和抗原性，降低其构象的灵活性，并有助于保持它们在unliganded构象。由此产生的下一代SOSIP.v5三聚体在兔中诱导强烈的自体2级中和抗体（NAb）应答。此外，BG 505 SOSIP.v6三聚体诱导了针对2级病毒亚组的弱异源NAb应答，而原型BG 505 SOSIP.664未诱导该应答。这些稳定化方法可应用于来自多个基因型的三聚体，作为旨在广泛诱导NAb（bNAb）的多价疫苗的组分。HIV-1包膜三聚体的稳定性可以通过基于结构的设计来增加设计改进适用于来自不同HIV-1分离株的包膜三聚体稳定的HIV-1包膜三聚体的免疫得到改进天然样HIV-1包膜三聚体是诱导广泛中和抗体的努力的平台。Torrents de la Peña et al.设计具有增强的稳定性和降低的灵活性的HIV-1包膜三聚体。这些经修饰的三聚体改善了中和抗体的诱导，并为引发广泛中和抗体提供了新的机会。
The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP.664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp)120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP.v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP.v6 trimers induced weak heterologous NAb responses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP.664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs). The stability of HIV-1 envelope trimers can be increased by structure-based design Design improvements are applicable to envelope trimers from different HIV-1 isolates Immunization of stabilized HIV-1 envelope trimers is improved Native-like HIV-1 envelope trimers are a platform for efforts to induce broadly neutralizing antibodies. Torrents de la Peña et al. design HIV-1 envelope trimers with enhanced stability and reduced flexibility. These modified trimers improve the induction of neutralizing antibodies and provide new opportunities toward elicitation of broadly neutralizing antibodies.
登录
查看更多内容
影响因子：
6.7
作者：
Klasse PJ;LaBranche CC;Ketas TJ;Ozorowski G;Cupo A;Pugach P;Ringe RP;Golabek M;van Gils MJ;Guttman M;Lee KK;Wilson IA;Butera ST;Ward AB;Montefiori DC;Sanders RW;Moore JP
通讯作者：
Moore JP
影响因子：
6.7
作者：
Derking R;Ozorowski G;Sliepen K;Yasmeen A;Cupo A;Torres JL;Julien JP;Lee JH;van Montfort T;de Taeye SW;Connors M;Burton DR;Wilson IA;Klasse PJ;Ward AB;Moore JP;Sanders RW
通讯作者：
Sanders RW
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
Sanders RW;Moore JP
通讯作者：
Moore JP
影响因子：
6.7
作者：
Guenaga J;de Val N;Tran K;Feng Y;Satchwell K;Ward AB;Wyatt RT
通讯作者：
Wyatt RT