Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C.
Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C.
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DOI：
10.1371/journal.ppat.1005864
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发表时间：
2016-09
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：
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
我们基于4株人类免疫缺陷病毒1型（HIV-1）分离株的env基因，研究了天然样、可溶性、重组SOSIP.664三聚体在家兔中的免疫原性；特别是BG505（进化支A）， B41（进化支B）， CZA97（进化支C）和DU422（进化支C）。不同的三聚体可以同时（作为a + B三聚体的混合物）或在73周内依次递送。对二价混合物中的进化支A和进化支B三聚体产生了自体的Tier-2中和抗体（NAb）反应。当将C三聚体作为增强免疫原给用A支和/或B支三聚体免疫的家兔时，C支三聚体也产生了自身的Tier-2 NAb反应，CZA97三聚体比DU422三聚体更强烈和一致。进化枝C三聚体也交叉促进了已有的NAb对进化枝A和B三聚体的反应。我们观察到异种Tier-2 NAb反应，尽管不一致，并且整体呼吸有限。然而，交叉中和的分支A BG505。T332N病毒在仅用B支三聚体免疫后再用C支三聚体增强的家兔中一致观察到。由BG505、B41和CZA97三聚体诱导的自体抗体主要识别同源病毒聚糖屏蔽上的特异性孔。这些空穴的共享位置可能解释了观察到的交叉促进效应和BG505的异源中和。T332N病毒。这些发现将指导进一步实验的设计，以确定多个Env三聚体是否以及如何共同诱导更广泛的中和抗体反应。原生样SOSIP三聚体是开发旨在诱导广泛中和抗体的免疫原的平台，因此可能是针对HIV-1感染的疫苗。以前没有研究报道过对一种以上三聚体的免疫反应。在这里，我们基于HIV-1分支A、B和C的病毒序列，评估了兔对两种或三种不同三聚体免疫的反应，以深入了解每种三聚体在不同方案下是否具有免疫原性。我们发现自体Tier-2中和抗体反应可以针对每种三聚体免疫原，无论它们是同时递送还是顺序递送。我们还观察到，当第二种三聚体随后被施用时，对第一种三聚体的中和反应有所增强。偶见交叉反应性中和抗体。我们还发现Env三聚体上的关键免疫原性表位涉及聚糖屏蔽上的孔，聚糖屏蔽通常保护病毒免受抗体结合。这些不同的发现将指导未来动物实验的设计，并最终用于人类。
We have investigated the immunogenicity in rabbits of native-like, soluble, recombinant SOSIP.664 trimers based on the env genes of four isolates of human immunodeficiency virus type 1 (HIV-1); specifically BG505 (clade A), B41 (clade B), CZA97 (clade C) and DU422 (clade C). The various trimers were delivered either simultaneously (as a mixture of clade A + B trimers) or sequentially over a 73-week period. Autologous, Tier-2 neutralizing antibody (NAb) responses were generated to the clade A and clade B trimers in the bivalent mixture. When delivered as boosting immunogens to rabbits immunized with the clade A and/or clade B trimers, the clade C trimers also generated autologous Tier-2 NAb responses, the CZA97 trimers doing so more strongly and consistently than the DU422 trimers. The clade C trimers also cross-boosted the pre-existing NAb responses to clade A and B trimers. We observed heterologous Tier-2 NAb responses albeit inconsistently, and with limited overall breath. However, cross-neutralization of the clade A BG505.T332N virus was consistently observed in rabbits immunized only with clade B trimers and then boosted with clade C trimers. The autologous NAbs induced by the BG505, B41 and CZA97 trimers predominantly recognized specific holes in the glycan shields of the cognate virus. The shared location of some of these holes may account for the observed cross-boosting effects and the heterologous neutralization of the BG505.T332N virus. These findings will guide the design of further experiments to determine whether and how multiple Env trimers can together induce more broadly neutralizing antibody responses. Native-like SOSIP trimers are a platform for development of immunogens aimed at inducing broadly neutralizing antibodies and, hence, a possible vaccine against HIV-1 infection. No previous study has reported on immune responses to more than one such trimer. Here, we assess how rabbits respond to immunization with two or three different trimers, based on virus sequences from HIV-1 clades A, B and C, to gain insights into whether each is immunogenic under various regimens. We find that autologous Tier-2 neutralizing antibody responses can be raised against each trimer immunogen, whether they are delivered simultaneously or sequentially. We also observed some boosting of the neutralization response to the first trimer when a second trimer was administered later. Cross-reactive neutralizing antibodies were seen but only sporadically. We also found that the key immunogenic epitopes on the Env trimers involved holes in the glycan shield, which normally protects the virus from antibody binding. These various findings will guide the design of future experiments in animals and eventually in humans.
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影响因子：
3.3
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1016/j.str.2015.07.020
发表时间：
2015-10-06
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Lee JH;de Val N;Lyumkis D;Ward AB
通讯作者：
Ward AB