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靶向V1V2环的抗体对HIV-1包膜三聚体的不对称识别

Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies.

作者信息

Wang Haoqing, Gristick Harry B, Scharf Louise, West Anthony P, Galimidi Rachel P, Seaman Michael S, Freund Natalia T, Nussenzweig Michel C, Bjorkman Pamela J

机构信息

Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.

Beth Israel Deaconess Medical Center, Boston, United States.

出版信息

Elife. 2017 May 26;6:e27389. doi: 10.7554/eLife.27389.

DOI:10.7554/eLife.27389
PMID:28548638
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5472438/
Abstract

The HIV-1 envelope (Env) glycoprotein binds to host cell receptors to mediate membrane fusion. The prefusion Env trimer is stabilized by V1V2 loops that interact at the trimer apex. Broadly neutralizing antibodies (bNAbs) against V1V2 loops, exemplified by PG9, bind asymmetrically as a single Fab to the apex of the symmetric Env trimer using a protruding CDRH3 to penetrate the Env glycan shield. Here we characterized a distinct mode of V1V2 epitope recognition by the new bNAb BG1 in which two Fabs bind asymmetrically per Env trimer using a compact CDRH3. Comparisons between cryo-EM structures of Env trimer complexed with BG1 (6.2 Å resolution) and PG9 (11.5 Å resolution) revealed a new V1V2-targeting strategy by BG1. Analyses of the EM structures provided information relevant to vaccine design including molecular details for different modes of asymmetric recognition of Env trimer and a binding model for BG1 recognition of V1V2 involving glycan flexibility.

摘要

HIV-1包膜（Env）糖蛋白与宿主细胞受体结合以介导膜融合。预融合Env三聚体由在三聚体顶端相互作用的V1V2环稳定。以PG9为例，针对V1V2环的广泛中和抗体（bNAb）作为单个Fab以不对称方式结合到对称Env三聚体的顶端，利用突出的互补决定区3（CDRH3）穿透Env聚糖屏蔽。在此，我们表征了新的bNAb BG1识别V1V2表位的独特模式，其中每个Env三聚体使用紧密的CDRH3以不对称方式结合两个Fab。与BG1复合的Env三聚体（分辨率为6.2 Å）和PG9（分辨率为11.5 Å）的冷冻电镜结构比较揭示了BG1靶向V1V2的新策略。对电镜结构的分析提供了与疫苗设计相关的信息，包括Env三聚体不同不对称识别模式的分子细节以及BG1识别V1V2涉及聚糖灵活性的结合模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/62911fa2ec85/elife-27389-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/db62a913593d/elife-27389-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/c64bed4fcfaf/elife-27389-fig3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/3395dd590c41/elife-27389-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/485221e290a6/elife-27389-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/984886093c4f/elife-27389-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/774cb65efee9/elife-27389-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/1491b9b0cdc8/elife-27389-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/413ce7849b2d/elife-27389-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/26932466e7cc/elife-27389-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/62911fa2ec85/elife-27389-resp-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/db62a913593d/elife-27389-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/272202b4c6da/elife-27389-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/8477a75f60e8/elife-27389-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/b2450b86efc8/elife-27389-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/c64bed4fcfaf/elife-27389-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/cd233a1eb1c3/elife-27389-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/3395dd590c41/elife-27389-fig3-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/485221e290a6/elife-27389-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/984886093c4f/elife-27389-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/774cb65efee9/elife-27389-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/1491b9b0cdc8/elife-27389-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/413ce7849b2d/elife-27389-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/26932466e7cc/elife-27389-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ebde/5472438/62911fa2ec85/elife-27389-resp-fig1.jpg

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