title: ORF7 of Varicella-Zoster Virus Is Required for Viral Cytoplasmic Envelopment in Differentiated Neuronal Cells.
abstract: Although a varicella-zoster virus (VZV) vaccine has been used for many years, the neuropathy caused by VZV infection is still a major health concern. Open reading frame 7 (ORF7) of VZV has been recognized as a neurotropic genein vivo, but its neurovirulent role remains unclear. In the present study, we investigated the effect of ORF7 deletion on VZV replication cycle at virus entry, genome replication, gene expression, capsid assembly and cytoplasmic envelopment, and transcellular transmission in differentiated neural progenitor cells (dNPCs) and neuroblastoma SH-SY5Y (dSY5Y) cells. Our results demonstrate that the ORF7 protein is a component of the tegument layer of VZV virions. Deleting ORF7 did not affect viral entry, viral genome replication, or the expression of typical viral genes but clearly impacted cytoplasmic envelopment of VZV capsids, resulting in a dramatic increase of envelope-defective particles and a decrease in intact virions. The defect was more severe in differentiated neuronal cells of dNPCs and dSY5Y. ORF7 deletion also impaired transmission of ORF7-deficient virus among the neuronal cells. These results indicate that ORF7 is required for cytoplasmic envelopment of VZV capsids, virus transmission among neuronal cells, and probably the neuropathy induced by VZV infection.IMPORTANCEThe neurological damage caused by varicella-zoster virus (VZV) reactivation is commonly manifested as clinical problems. Thus, identifying viral neurovirulent genes and characterizing their functions are important for relieving VZV related neurological complications. ORF7 has been previously identified as a potential neurotropic gene, but its involvement in VZV replication is unclear. In this study, we found that ORF7 is required for VZV cytoplasmic envelopment in differentiated neuronal cells, and the envelopment deficiency caused by ORF7 deletion results in poor dissemination of VZV among neuronal cells. These findings imply that ORF7 plays a role in neuropathy, highlighting a potential strategy to develop a neurovirulence-attenuated vaccine against chickenpox and herpes zoster and providing a new target for intervention of neuropathy induced by VZV.
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Hai-Fei
authors.initials: HF
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Wen-Bo
authors.initials: WB
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Zhang-Zhou
authors.initials: ZZ
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Yi-Ge
authors.initials: YG
authors.lastname: Song
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Xi-Juan
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Jin-Yan
authors.initials: JY
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Fei-Long
authors.initials: FL
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Simon
authors.initials: S
authors.lastname: Rayner
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, New Jersey, USA zhuhu@njms.rutgers.edu luomh@wh.iov.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Virology, CAS Center for Excellence in Brain Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China zhuhu@njms.rutgers.edu luomh@wh.iov.cn.|University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Luo
mesh_terms: D002213:Capsid / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003593:Cytoplasm / Q000821:virology; D017353:Gene Deletion; D016679:Genome, Viral; D006562:Herpes Zoster / Q000821:virology; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology* / Q000821:virology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*; D014771:Virion; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: C553585:ORF7 protein, human herpesvirus 3; D014759:Viral Envelope Proteins; D014764:Viral Proteins
keywords: ORF7; cytoplasmic envelopment; differentiated SH-SY5Y cells; differentiated neural progenitor cells; varicella-zoster virus