Generation and preliminary characterization of vertebrate-specific replication-defective Zika virus

Wan, Shengfeng; Cao, Shengbo; Wang, Xugang; Zhou, Yanfei; Yan, Weidong; Gu, Xing; Wu, T. C.; Pang, Xiaowu

doi:10.1016/j.virol.2020.09.001

Cited by 4 publications

(9 citation statements)

References 55 publications

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“…Structural and functional mapping of the furin cleavage sites revealed the importance of furin and its preference ( 21 , 23 , 24 ). Previous studies in our laboratory have demonstrated that mutations in furin cleavage sites and nearby lead to alterations in ZIKV replication and virulence ( 22 ). Therefore, the similar mutant, JEV prM-S78R-K79R-S81R, was constructed using the full-length JEV cDNA clone.…”

Section: Resultsmentioning

confidence: 99%

“…The multibasic amino acid motif is not a sufficient requirement for the efficient furin proteolysis of the substrate protein, and the amino acids located at the P7, P6, P5, P3, and P1’ to P4’ oppositions are very important for modulating furin cleavage efficiency ( 21 ). Previous studies in our laboratory have demonstrated that mutations in furin cleavage sites and its nearby lead to alterations in ZIKV replication and virulence ( 22 ). Therefore, the similar mutations in prM of JEV were constructed to evaluate the relationship between prM cleavage and viral replication or virulence in our study.…”

Section: Introductionmentioning

confidence: 99%

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Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

et al. 2022

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

et al. 2022

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“…In our previous study, a high-dose challenge with VSRD-ZIKV was safe in newborn and three-week-old immunocompromised mice [ 23 ]. Given the high level of safety exhibited by VSRD-ZIKV, we next assessed the protective efficacy of a single delivery and prime-boost VSRD-ZIKV vaccination regimen in five-week-old AG129 mice.…”

Section: Resultsmentioning

confidence: 99%

“…Zika virus (MR766 strain) was purchased from ATCC. VSRD-ZIKV was derived from ZIKV/MR766 by a combination of reverse genetics and host-specific adaptation [ 23 ]. Dr. Qiyi Tang kindly provided ZIKV from Puerto Rico (PRVABC59).…”

Section: Methodsmentioning

confidence: 99%

“…However, single-cycle, encapsidation-defective viruses require complicated packaging systems [ 21 ] or helper viral replicons [ 22 ], making the development of a licensed commercial vaccine difficult. Recently, we converted a dual-host ZIKV into a vertebrate-specific replication-defective ZIKV (VSRD-ZIKV) and demonstrated its inherently high level of safety in immunocompromised mice [ 23 ]. Therefore, the VSRD-ZIKV can replicate efficiently in mosquito-derived C6/36 cells and overcome packaging cell dependence to produce encapsidation-defective viruses.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Vertebrate-Specific Replication-Defective Zika Virus, a Novel Single-Cycle Arbovirus Vaccine, in a Mouse Model

et al. 2021

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The flavivirus Zika (ZIKV) has emerged as a global threat, making the development of a ZIKV vaccine a priority. While live-attenuated vaccines are known to induce long-term immunity but reduced safety, inactivated vaccines exhibit a weaker immune response as a trade-off for increased safety margins. To overcome the trade-off between immunogenicity and safety, the concept of a third-generation flavivirus vaccine based on single-cycle flaviviruses has been developed. These third-generation flavivirus vaccines have demonstrated extreme potency with a high level of safety in animal models. However, the production of these single-cycle, encapsidation-defective flaviviruses requires a complicated virion packaging system. Here, we investigated a new single-cycle flavivirus vaccine, a vertebrate-specific replication-defective ZIKV (VSRD-ZIKV), in a mouse model. VSRD-ZIKV replicates to high titers in insect cells but can only initiate a single-round infection in vertebrate cells. During a single round of infection, VSRD-ZIKV can express all the authentic viral antigens in vertebrate hosts. VSRD-ZIKV immunization elicited a robust cellular and humoral immune response that protected against a lethal ZIKV challenge in AG129 mice. Additionally, VSRD-ZIKV-immunized pregnant mice were protected against vertically transferring a lethal ZIKV infection to their offspring. Immunized male mice were protected and prevented viral accumulation in the testes after being challenged with lethal ZIKV. Overall, our results indicate that VSRD-ZIKV induces a potent protective immunity against ZIKV in a mouse model and represents a promising approach to develop novel single-cycle arbovirus vaccines.

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Divergent pathogenic dynamics of immature tick-borne and mosquito-borne flaviviruses: a paradigm shift in prM-containing particle infectivity

Ruzek,

Holoubek,

Salat

et al. 2024

Preprint

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Maturing flaviviruses undergo pH-dependent conformational changes, transitioning from trimeric pre-membrane protein prM and envelope protein E (prM-E) complexes to dimeric E with cleaved prM. However, little is known about the intermediate maturation stages and whether immature virions contribute to infection. Here we demonstrated that immature prM-containing particles of tick-borne flaviviruses—tick-borne encephalitis virus (TBEV), Langat virus, and louping ill virus—exhibited infectivity in mammalian cells under physiological conditions. This finding challenges the long-standing assumption that prM-containing flavivirus particles are non-infectious, as is the case for immature mosquito-borne flaviviruses, including Usutu virus, Zika virus, and West Nile virus (WNV). In a mouse model, prM-TBEV exhibited high pathogenicity, contrasting with the reduced pathogenicity of prM-WNV. Structural modelling, functional validation, and site-directed mutagenesis revealed interactions within the prM-E complex that influence pH sensitivity, furin cleavage site accessibility, and virus infectivity. This study, therefore, elucidates the distinctive dynamics of infectivity of tick- and mosquito-borne flaviviruses.

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Generation and preliminary characterization of vertebrate-specific replication-defective Zika virus

Cited by 4 publications

References 55 publications

Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

Increased Cleavage of Japanese Encephalitis Virus prM Protein Promotes Viral Replication but Attenuates Virulence

Evaluation of Vertebrate-Specific Replication-Defective Zika Virus, a Novel Single-Cycle Arbovirus Vaccine, in a Mouse Model

Divergent pathogenic dynamics of immature tick-borne and mosquito-borne flaviviruses: a paradigm shift in prM-containing particle infectivity

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