Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis

ABSTRACT Compared with other flaviviruses, Zika virus (ZIKV) is uniquely associated with congenital diseases in pregnant women. One recent study reported that (i) ZIKV has higher thermostability than dengue virus (DENV [a flavivirus closely related to ZIKV]), which might contribute to the disease ou...

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Autores principales:	Xuping Xie, Yujiao Yang, Antonio E. Muruato, Jing Zou, Chao Shan, Bruno T. D. Nunes, Daniele B. A. Medeiros, Pedro F. C. Vasconcelos, Scott C. Weaver, Shannan L. Rossi, Pei-Yong Shi
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/49c9b1a7b7b548d5b2d07e51175a25ce
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spelling	oai:doaj.org-article:49c9b1a7b7b548d5b2d07e51175a25ce2021-11-15T15:51:06ZUnderstanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis10.1128/mBio.02134-162150-7511https://doaj.org/article/49c9b1a7b7b548d5b2d07e51175a25ce2017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02134-16https://doaj.org/toc/2150-7511ABSTRACT Compared with other flaviviruses, Zika virus (ZIKV) is uniquely associated with congenital diseases in pregnant women. One recent study reported that (i) ZIKV has higher thermostability than dengue virus (DENV [a flavivirus closely related to ZIKV]), which might contribute to the disease outcome; (ii) the higher thermostability of ZIKV could arise from an extended loop structure in domain III of the viral envelope (E) protein and an extra hydrogen-bond interaction between E molecules (V. A. Kostyuchenko, E. X. Y. Lim, S. Zhang, G. Fibriansah, T.-S. Ng, J. S. G. Ooi, J. Shi, and S.-M. Lok, Nature 533:425–428, 2016, https://doi.org/10.1038/nature17994 ). Here we report the functional analysis of the structural information in the context of complete ZIKV and DENV-2 virions. Swapping the prM-E genes between ZIKV and DENV-2 switched the thermostability of the chimeric viruses, identifying the prM-E proteins as the major determinants for virion thermostability. Shortening the extended loop of the E protein by 1 amino acid was lethal for ZIKV assembly/release. Mutations (Q350I and T351V) that abolished the extra hydrogen-bond interaction between the E proteins did not reduce ZIKV thermostability, indicating that the extra interaction does not increase the thermostability. Interestingly, mutant T351V was attenuated in A129 mice defective in type I interferon receptors, even though the virus retained the wild-type thermostability. Furthermore, we found that a chimeric ZIKV with the DENV-2 prM-E and a chimeric DENV-2 with the ZIKV prM-E were highly attenuated in A129 mice; these chimeric viruses were highly immunogenic and protective against DENV-2 and ZIKV challenge, respectively. These results indicate the potential of these chimeric viruses for vaccine development. IMPORTANCE Analysis of a recently observed high-resolution structure of ZIKV led to a hypothesis that its unusual stability may contribute to the associated, unique disease outcomes. Here we performed a functional analysis to demonstrate that viral prM-E genes are the main determinants for the high stability of ZIKV. The extra hydrogen-bond interaction (observed in the high-resolution structure) between ZIKV E proteins did not enhance virion stability, whereas the extended loop of E protein (CD loop in domain III) was essential for ZIKV assembly. More importantly, we found that a chimeric ZIKV with DENV-2 prM-E genes and a chimeric DENV-2 with ZIKV prM-E genes were highly attenuated in A129 mice. Mice immunized with these chimeric viruses generated robust neutralizing antibody responses and were fully protected from DENV-2 and ZIKV challenge, respectively, indicating that these chimeric viruses could be further developed as vaccine candidates.Xuping XieYujiao YangAntonio E. MuruatoJing ZouChao ShanBruno T. D. NunesDaniele B. A. MedeirosPedro F. C. VasconcelosScott C. WeaverShannan L. RossiPei-Yong ShiAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Xuping Xie Yujiao Yang Antonio E. Muruato Jing Zou Chao Shan Bruno T. D. Nunes Daniele B. A. Medeiros Pedro F. C. Vasconcelos Scott C. Weaver Shannan L. Rossi Pei-Yong Shi Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
description	ABSTRACT Compared with other flaviviruses, Zika virus (ZIKV) is uniquely associated with congenital diseases in pregnant women. One recent study reported that (i) ZIKV has higher thermostability than dengue virus (DENV [a flavivirus closely related to ZIKV]), which might contribute to the disease outcome; (ii) the higher thermostability of ZIKV could arise from an extended loop structure in domain III of the viral envelope (E) protein and an extra hydrogen-bond interaction between E molecules (V. A. Kostyuchenko, E. X. Y. Lim, S. Zhang, G. Fibriansah, T.-S. Ng, J. S. G. Ooi, J. Shi, and S.-M. Lok, Nature 533:425–428, 2016, https://doi.org/10.1038/nature17994 ). Here we report the functional analysis of the structural information in the context of complete ZIKV and DENV-2 virions. Swapping the prM-E genes between ZIKV and DENV-2 switched the thermostability of the chimeric viruses, identifying the prM-E proteins as the major determinants for virion thermostability. Shortening the extended loop of the E protein by 1 amino acid was lethal for ZIKV assembly/release. Mutations (Q350I and T351V) that abolished the extra hydrogen-bond interaction between the E proteins did not reduce ZIKV thermostability, indicating that the extra interaction does not increase the thermostability. Interestingly, mutant T351V was attenuated in A129 mice defective in type I interferon receptors, even though the virus retained the wild-type thermostability. Furthermore, we found that a chimeric ZIKV with the DENV-2 prM-E and a chimeric DENV-2 with the ZIKV prM-E were highly attenuated in A129 mice; these chimeric viruses were highly immunogenic and protective against DENV-2 and ZIKV challenge, respectively. These results indicate the potential of these chimeric viruses for vaccine development. IMPORTANCE Analysis of a recently observed high-resolution structure of ZIKV led to a hypothesis that its unusual stability may contribute to the associated, unique disease outcomes. Here we performed a functional analysis to demonstrate that viral prM-E genes are the main determinants for the high stability of ZIKV. The extra hydrogen-bond interaction (observed in the high-resolution structure) between ZIKV E proteins did not enhance virion stability, whereas the extended loop of E protein (CD loop in domain III) was essential for ZIKV assembly. More importantly, we found that a chimeric ZIKV with DENV-2 prM-E genes and a chimeric DENV-2 with ZIKV prM-E genes were highly attenuated in A129 mice. Mice immunized with these chimeric viruses generated robust neutralizing antibody responses and were fully protected from DENV-2 and ZIKV challenge, respectively, indicating that these chimeric viruses could be further developed as vaccine candidates.
format	article
author	Xuping Xie Yujiao Yang Antonio E. Muruato Jing Zou Chao Shan Bruno T. D. Nunes Daniele B. A. Medeiros Pedro F. C. Vasconcelos Scott C. Weaver Shannan L. Rossi Pei-Yong Shi
author_facet	Xuping Xie Yujiao Yang Antonio E. Muruato Jing Zou Chao Shan Bruno T. D. Nunes Daniele B. A. Medeiros Pedro F. C. Vasconcelos Scott C. Weaver Shannan L. Rossi Pei-Yong Shi
author_sort	Xuping Xie
title	Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
title_short	Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
title_full	Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
title_fullStr	Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
title_full_unstemmed	Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis
title_sort	understanding zika virus stability and developing a chimeric vaccine through functional analysis
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/49c9b1a7b7b548d5b2d07e51175a25ce
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Understanding Zika Virus Stability and Developing a Chimeric Vaccine through Functional Analysis

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