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DNA 表达稳定的天然样 HIV-1 包膜三聚体的合理设计。

Rational Design of DNA-Expressed Stabilized Native-Like HIV-1 Envelope Trimers.

机构信息

Imperial College London, Department of Medicine, Division of Infectious Diseases, Section of Virology, Norfolk Place, London W2 1PG, UK.

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK.

出版信息

Cell Rep. 2018 Sep 18;24(12):3324-3338.e5. doi: 10.1016/j.celrep.2018.08.051.

DOI:10.1016/j.celrep.2018.08.051
PMID:30232012
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6167709/
Abstract

The HIV-1-envelope glycoprotein (Env) is the main target of antigen design for antibody-based prophylactic vaccines. The generation of broadly neutralizing antibodies (bNAb) likely requires the appropriate presentation of stabilized trimers preventing exposure of non-neutralizing antibody (nNAb) epitopes. We designed a series of membrane-bound Envs with increased trimer stability through the introduction of key stabilization mutations. We derived a stabilized HIV-1 trimer, ConSOSL.UFO.750, which displays a dramatic reduction in nNAb binding while maintaining high quaternary and MPER-specific bNAb binding. Its soluble counterpart, ConSOSL.UFO.664, displays similar antigenicity, and its native-like Env structure is confirmed by negative stain-EM and glycosylation profiling of the soluble ConSOSL.UFO.664 trimer. A rabbit immunization study demonstrated that the ConSOSL.UFO.664 can induce autologous tier 2 neutralization. We have successfully designed a stabilized native-like Env trimer amenable to nucleic acid or viral vector-based vaccination strategies.

摘要

HIV-1 包膜糖蛋白（Env）是基于抗体的预防性疫苗抗原设计的主要目标。产生广泛中和抗体（bNAb）可能需要适当展示稳定的三聚体，以防止非中和抗体（nNAb）表位的暴露。我们通过引入关键稳定突变设计了一系列膜结合的 Env，以提高三聚体稳定性。我们得到了一种稳定的 HIV-1 三聚体 ConSOSL.UFO.750，它显示出 nNAb 结合的显著减少，同时保持高四级和 MPER 特异性 bNAb 结合。其可溶性对应物 ConSOSL.UFO.664 具有相似的抗原性，其天然样 Env 结构通过负染电镜和可溶性 ConSOSL.UFO.664 三聚体的糖基化分析得到证实。兔免疫研究表明，ConSOSL.UFO.664 可以诱导同源二级中和。我们已经成功设计了一种稳定的天然样 Env 三聚体，适用于核酸或病毒载体为基础的疫苗接种策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/501173178c54/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/cd7d42e3d7a3/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/b069f0652d85/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/059939ec61f0/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/0eb2a7b63d8f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/c7c060e9dfc5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/f3fb327e2dd8/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/afb16a1576d8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/501173178c54/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/cd7d42e3d7a3/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/b069f0652d85/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/059939ec61f0/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/0eb2a7b63d8f/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/c7c060e9dfc5/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/f3fb327e2dd8/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/afb16a1576d8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3706/6167709/501173178c54/gr7.jpg

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