A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies.
A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies.
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DOI：
10.1371/journal.ppat.1003618
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发表时间：
2013-09
期刊：
影响因子：
6.7
通讯作者：
Moore JP
中科院分区：
文献类型：
--
作者：
Sanders RW;Derking R;Cupo A;Julien JP;Yasmeen A;de Val N;Kim HJ;Blattner C;de la Peña AT;Korzun J;Golabek M;de Los Reyes K;Ketas TJ;van Gils MJ;King CR;Wilson IA;Ward AB;Klasse PJ;Moore JP
人类免疫缺陷病毒1型（HIV-1）候选疫苗的一个理想但尚未实现的特性是诱导广泛中和抗体（bNAb）的能力。解决该问题的一种方法是产生天然包膜糖蛋白（Env）刺突的三聚体模拟物，其暴露尽可能多的bNAb表位，同时封闭非中和抗体（非NAb）的那些表位。在这里，我们描述了可溶性的，切割的SOSIP.664 gp 140三聚体的基础上亚型A传播/创始人菌株，BG 505的设计和性能。这些三聚体是高度稳定的，甚至比相应的gp 120单体，如差示扫描量热法判断。当通过负染色电子显微镜（EM）观察时，它们也是同质的并且非常类似于天然病毒刺突。我们使用了几种技术，包括ELISA和表面等离子体共振（SPR），以确定单克隆抗体（MAbs）的能力，结合可溶性三聚体和中和相应的病毒之间的关系。总体而言，一致性极佳，因为几乎所有针对HIV-1 Env上多个中和表位的bNAb均与BG 505 SOSIP. 664 gp 140三聚体（包括四级表位（CH 01、PG 9、PG 16和PG T 145））具有高度反应性。相反，CD 4结合位点的非NAb、CD 4诱导的表位或gp 41 ECTO不与三聚体反应，即使它们的表位存在于Env的更简单形式（例如gp 120单体或解离的gp 41亚基）上。然而，针对V3表位的三种非中和性MAb确实与三聚体强烈反应，但仅通过ELISA，并且根本不通过SPR，并且仅在有限程度上通过EM。这些新的可溶性三聚体可用于结构研究，并正在评估其作为免疫原的性能。迫切需要一种保护性的HIV-1疫苗，但尚未有候选疫苗提供足够的抗感染保护。大多数现有的疫苗通过诱导中和抗体提供免疫保护，这也是许多HIV-1免疫原设计项目的目标。HIV-1表面上的三聚体包膜蛋白复合物是中和抗体的唯一相关靶标，并且是针对其诱导的大多数策略的基础。然而，制备充分模拟病毒上存在的结构的可溶性重组包膜蛋白复合物一直具有挑战性。在这里，我们描述了一种新设计和工程化的Env蛋白，具有适当的特性。这种蛋白质，称为BG 505 SOSIP.664 gp 140，结合大多数已知的中和抗体，但通常不结合缺乏中和活性的抗体。它在负染电子显微镜照片中的外观也类似于天然包膜复合物。
A desirable but as yet unachieved property of a human immunodeficiency virus type 1 (HIV-1) vaccine candidate is the ability to induce broadly neutralizing antibodies (bNAbs). One approach to the problem is to create trimeric mimics of the native envelope glycoprotein (Env) spike that expose as many bNAb epitopes as possible, while occluding those for non-neutralizing antibodies (non-NAbs). Here, we describe the design and properties of soluble, cleaved SOSIP.664 gp140 trimers based on the subtype A transmitted/founder strain, BG505. These trimers are highly stable, more so even than the corresponding gp120 monomer, as judged by differential scanning calorimetry. They are also homogenous and closely resemble native virus spikes when visualized by negative stain electron microscopy (EM). We used several techniques, including ELISA and surface plasmon resonance (SPR), to determine the relationship between the ability of monoclonal antibodies (MAbs) to bind the soluble trimers and neutralize the corresponding virus. In general, the concordance was excellent, in that virtually all bNAbs against multiple neutralizing epitopes on HIV-1 Env were highly reactive with the BG505 SOSIP.664 gp140 trimers, including quaternary epitopes (CH01, PG9, PG16 and PGT145). Conversely, non-NAbs to the CD4-binding site, CD4-induced epitopes or gp41ECTO did not react with the trimers, even when their epitopes were present on simpler forms of Env (e.g. gp120 monomers or dissociated gp41 subunits). Three non-neutralizing MAbs to V3 epitopes did, however, react strongly with the trimers but only by ELISA, and not at all by SPR and to only a limited extent by EM. These new soluble trimers are useful for structural studies and are being assessed for their performance as immunogens. A protective HIV-1 vaccine is badly needed, but no candidate has yet provided an adequate level of protection against infection. Most existing vaccines provide immune protection by inducing neutralizing antibodies, also a goal of many HIV-1 immunogen design projects. The trimeric envelope protein complex on the HIV-1 surface is the only relevant target for neutralizing antibodies, and is the basis for most strategies aimed at their induction. However, making a soluble, recombinant envelope protein complex that adequately mimics the structure present on the virus has been challenging. Here, we describe a newly designed and engineered Env protein that has the appropriate properties. This protein, termed BG505 SOSIP.664 gp140, binds most of the known neutralizing antibodies but generally does not bind antibodies that lack neutralization activity. Its appearance in negative stain electron micrographs also resembles native envelope complexes.
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