Rational design of West Nile virus vaccine through large replacement of 3′ UTR with internal poly(A)

Zhang, Yanan; Li, Na; Zhang, Qiuyan; Liu, Jing; Zhan, Shun-Li; Gao, Lei; Zeng, Xiang-Yue; Fang, Yu; Zhang, Hongqing; Li, Xiaodan; Deng, Cheng-Lin; Shi, Pei–Yong; Yuan, Zhiming; Ye, Han-Qing; Zhang, Bo

doi:10.15252/emmm.202114108

Cited by 11 publications

(4 citation statements)

References 57 publications

(62 reference statements)

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“…The structure of flavivirus 3’ UTR and the production of sfRNAs have been reported as one of important determinants of viral pathogenicity [ 9 , 11 ]. Our recent study identified that a WNV mutant carrying a replacement of SL and DB domains of 3′ UTR with internal poly(A) tract was highly attenuate [ 32 ]. Although DB-dup virus contained duplicated DB sequences, there was still a large fragment of SL domain missing from its genome.…”

Section: Resultsmentioning

confidence: 99%

Sequence duplication in 3′ UTR modulates virus replication and virulence of Japanese encephalitis virus

Zhang

Liu

et al. 2021

Emerging Microbes & Infections

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Japanese encephalitis virus (JEV), an important neurotropic pathogen, belongs to the genus Flavivirus of the family Flaviviridae and has caused huge threat to public health. It is still obscure regarding the functions of stem-loop (SL) and dumbbell (DB) domains of JEV 3′ UTR in viral replication and virulence. In the current study, using the infectious clone of JEV SA14 strain as a backbone, we constructed a series of deletion mutants of 3′ UTR to investigate their effects on virus replication. The results showed that partial deletions within SL or DB domain had no apparent effects on virus replication in both mammalian (BHK-21) and mosquito (C6/36) cells, suggesting that they were not involved in viral host-specific replication. However, the entire SL domain deletion (ΔVR) significantly reduced virus replication in both cell lines, indicating the important role of the complete SL domain in virus replication. The revertant of ΔVR mutant virus was obtained by serial passage in BHK-21 cells that acquired a duplication of DB domain (DB-dup) in the 3′ UTR, which greatly restored virus replication as well as the capability to produce the subgenomic flavivirus RNAs (sfRNAs). Interestingly, the DB-dup mutant virus was highly attenuated in C57BL/6 mice despite replicating similar to WT JEV. These findings demonstrate the significant roles of the duplicated structures in 3′ UTR in JEV replication and provide a novel strategy for the design of live-attenuated vaccines.

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Section: Resultsmentioning

confidence: 99%

Sequence duplication in 3′ UTR modulates virus replication and virulence of Japanese encephalitis virus

Zhang

Liu

et al. 2021

Emerging Microbes & Infections

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“…The reverse genetics system is a powerful molecular tool for RNA virus research and vaccine development. Infectious clones of flaviviruses such as Zika virus (ZIKV) and West Nile virus (WNV) have been successfully constructed and rationally engineered for vaccine design [45,46]. As ISFVs can only infect arthropod vectors and not the vertebrate hosts, they represent identical viral vectors for vaccine development.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Characterization of a New Strain of Mosquito Flavivirus Derived from Culicoides

Huang

Zhang

et al. 2022

Viruses

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Mosquito-specific flaviviruses comprise a group of insect-specific viruses with a single positive RNA, which can affect the duplication of mosquito-borne viruses and the life growth of mosquitoes, and which have the potential to be developed as a vaccine platform for mosquito-borne viruses. In this study, a strain of mosquito flavivirus (MFV) YN15-283-02 was detected in Culicoides collected from Yunnan, China. The isolation of the purified MFV YN15-283-02 from cell culture failed, and the virus was then rescued by an infectious clone. To study the biological features of MFV YN15-283-02 in vitro and in vivo, electron microscopy, phylogenetic tree, and viral growth kinetic analyses were performed in both cell lines and mosquitoes. The rescued MFV (rMFV) YN15-283-02 duplicated and reached a peak in C6/36 cells at 6 d.p.i. with approximately 2 × 106 RNA copies/μL (RNA to cell ratio of 0.1), but without displaying a cytopathic effect. In addition, the infection rate for the rMFV in Ae.aegypti show a low level in both larvae (≤15%) and adult mosquitoes (≤12%).

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“…Moreover, 3 SL is the only structure in the 3 UTR that is absolutely needed for viral production. Keeping only the 3 SL and replacing all other parts of the 3 UTR with an appropriate length of poly (A) sequence in WNV RNA results in a highly attenuated but viable virus [28].…”

Section: The Roles Of Domain 3 and 2 In Denv Rna Replicationmentioning

confidence: 99%

Subgenomic Flaviviral RNAs of Dengue Viruses

Liu,

Guan,

Liu

2023

Viruses

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Subgenomic flaviviral RNAs (sfRNAs) are produced during flavivirus infections in both arthropod and vertebrate cells. They are undegraded products originating from the viral 3′ untranslated region (3′ UTR), a result of the action of the host 5′-3′ exoribonuclease, Xrn1, when it encounters specific RNA structures known as Xrn1-resistant RNAs (xrRNAs) within the viral 3′ UTR. Dengue viruses generate three to four distinct species of sfRNAs through the presence of two xrRNAs and two dumbbell structures (DBs). The tertiary structures of xrRNAs have been characterized to form a ringlike structure around the 5′ end of the viral RNA, effectively inhibiting the activity of Xrn1. The most important role of DENV sfRNAs is to inhibit host antiviral responses by interacting with viral and host proteins, thereby influencing viral pathogenicity, replicative fitness, epidemiological fitness, and transmission. In this review, we aimed to summarize the biogenesis, structures, and functions of DENV sfRNAs, exploring their implications for viral interference.

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Rational design of West Nile virus vaccine through large replacement of 3′ UTR with internal poly(A)

Cited by 11 publications

References 57 publications

Sequence duplication in 3′ UTR modulates virus replication and virulence of Japanese encephalitis virus

Sequence duplication in 3′ UTR modulates virus replication and virulence of Japanese encephalitis virus

In Vitro and In Vivo Characterization of a New Strain of Mosquito Flavivirus Derived from Culicoides

Subgenomic Flaviviral RNAs of Dengue Viruses

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