دورية أكاديمية
Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B
| العنوان: | Crystal Structure and Immunogenicity of the DS-Cav1-Stabilized Fusion Glycoprotein From Respiratory Syncytial Virus Subtype B |
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| المؤلفون: | M. Gordon Joyce, Amy Bao, Man Chen, Ivelin S. Georgiev, Li Ou, Tatsiana Bylund, Aliaksandr Druz, Wing-Pui Kong, Dongjun Peng, Emily J. Rundlet, Joseph G. Van Galen, Shuishu Wang, Yongping Yang, Baoshan Zhang, Gwo-Yu Chuang, Jason S. McLellan, Barney S. Graham, John R. Mascola, Peter D. Kwong |
| المصدر: | Pathogens and Immunity, Vol 4, Iss 2, Pp 294-323 (2019) |
| بيانات النشر: | Case Western Reserve University, 2019. |
| سنة النشر: | 2019 |
| المجموعة: | LCC:Pathology LCC:Immunologic diseases. Allergy |
| مصطلحات موضوعية: | antigenic site, crystal structure, epitope, fusion glycoprotein, immunogenicity, neutralization, rsv subtype, vaccine, Pathology, RB1-214, Immunologic diseases. Allergy, RC581-607 |
| الوصف: | Background: Respiratory syncytial virus (RSV) subtypes, A and B, co-circulate in annual epidemics and alternate in dominance. We have shown that a subtype A RSV fusion (F) glycoprotein, stabilized in its prefusion conformation by DS-Cav1 mutations, is a promising RSV-vaccine immunogen, capable of boosting RSV-neutralizing titers in healthy adults. In both humans and vaccine-tested animals, neutralizing titers elicited by this subtype A DS-Cav1 immunogen were ~ 2- to 3-fold higher against the homologous subtype A virus than against the heterologous subtype B virus. Methods: To understand the molecular basis for this subtype difference, we introduced DS-Cav1 mutations into RSV strain B18537 F, determined the trimeric crystal structure, and carried out immunogenicity studies. Results: The B18537 DS-Cav1 F structure at 2-Å resolution afforded a precise delineation of prefusion F characteristics, including those of antigenic site Ø, a key trimer-apex site. Structural comparison with the subtype A prefusion F indicated 11% of surface residues to be different, with an alpha-carbon root-mean-square deviation (RMSD) of 1.2 Å; antigenic site Ø, however, resulted in 23% of its surface residues and had an alpha-carbon RMSD of 2.2 Å. Immunization of vaccine-tested animals with DS-Cav1-stabilized B18537 F induced neutralizing responses ~100-fold higher than with postfusion B18537 F. Notably, elicited responses neutralized RSV subtypes A and B at similar levels and were directed towards both conserved equatorial and diverse apical regions. Conclusion: We propose that structural differences in apical and equatorial sites–coupled to differently focused immune responses–provide a molecular explanation for observed differences in elicited subtype A and B neutralizing responses. Keywords: antigenic site; crystal structure; epitope; fusion glycoprotein; immunogenicity; neutralization; RSV subtype; vaccine |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2469-2964 |
| Relation: | https://paijournal.com/index.php/paijournal/article/view/338; https://doaj.org/toc/2469-2964 |
| DOI: | 10.20411/pai.v4i2.338 |
| URL الوصول: | https://doaj.org/article/aa9225bfc40c4f49a0f6918637f4fc7d |
| رقم الأكسشن: | edsdoj.9225bfc40c4f49a0f6918637f4fc7d |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 24692964 |
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| DOI: | 10.20411/pai.v4i2.338 |