气候变化领域集成服务门户(CCPortal): Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer

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DOI	10.1073/pnas.2015149118
	Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer
	Guest J.D.; Wang R.; Elkholy K.H.; Chagas A.; Chao K.L.; Cleveland T.E.; Kim Y.C.; Keck Z.-Y.; Marin A.; Yunus A.S.; Mariuzza R.A.; Andrianov A.K.; Toth E.A.; Foung S.K.H.; Pierce B.G.; Fuerst T.R.
发表日期	2021
ISSN	00278424
卷号	118 期号:3
英文摘要	Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine development. However, the E1E2 transmembrane domains that are critical for native assembly make it challenging to produce this complex in a homogenous soluble form that is reflective of its state on the viral envelope. To enable rational design of an E1E2 vaccine, as well as structural characterization efforts, we have designed a soluble, secreted form of E1E2 (sE1E2). As with soluble glycoprotein designs for other viruses, it incorporates a scaffold to enforce assembly in the absence of the transmembrane domains, along with a furin cleavage site to permit native-like heterodimerization. This sE1E2 was found to assemble into a form closer to its expected size than full-length E1E2. Preservation of native structural elements was confirmed by high-affinity binding to a panel of conformationally specific monoclonal antibodies, including two neutralizing antibodies specific to native E1E2 and to its primary receptor, CD81. Finally, sE1E2 was found to elicit robust neutralizing antibodies in vivo. This designed sE1E2 can both provide insights into the determinants of native E1E2 assembly and serve as a platform for production of E1E2 for future structural and vaccine studies, enabling rational optimization of an E1E2-based antigen. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Hepatitis C virus \| envelope glycoprotein \| vaccine \| E1E2 \| scaffold
语种	英语
scopus关键词	CD81 antigen; furin; monoclonal antibody; neutralizing antibody; protein E1E2; unclassified drug; virus glycoprotein; animal experiment; animal model; Article; binding affinity; controlled study; female; hepatitis C; Hepatitis C virus; heterodimerization; human; in vivo study; mouse; nonhuman; priority journal; protein analysis; protein assembly; protein cleavage; protein conformation; protein secretion; protein synthesis
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180955
作者单位	Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, United States; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, United States; Molecular Biology Department, Genetic Engineering and Biotechnology Division, National Research Centre, Cairo, 12622, Egypt; Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD 20899, United States; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States
推荐引用方式 GB/T 7714	Guest J.D.,Wang R.,Elkholy K.H.,et al. Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer[J],2021,118(3).
APA	Guest J.D..,Wang R..,Elkholy K.H..,Chagas A..,Chao K.L..,...&Fuerst T.R..(2021).Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Guest J.D.,et al."Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).