scholarly journals Current In Vitro Models to Study Varicella Zoster Virus Latency and Reactivation

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 103 ◽  
Author(s):  
Nicholas Baird ◽  
Shuyong Zhu ◽  
Catherine Pearce ◽  
Abel Viejo-Borbolla
Keyword(s):  
Varicella Zoster Virus ◽  
In Vitro Models ◽  
Varicella Zoster ◽  
Peripheral Neurons ◽  
Virus Latency ◽  
Human Neurons ◽  
Life Threatening ◽  
Phosphoinositide 3 Kinase ◽  
Human Specific

Varicella zoster virus (VZV) is a highly prevalent human pathogen that causes varicella (chicken pox) during primary infection and establishes latency in peripheral neurons. Symptomatic reactivation often presents as zoster (shingles), but it has also been linked to life-threatening diseases such as encephalitis, vasculopathy and meningitis. Zoster may be followed by postherpetic neuralgia, neuropathic pain lasting after resolution of the rash. The mechanisms of varicella zoster virus (VZV) latency and reactivation are not well characterized. This is in part due to the human-specific nature of VZV that precludes the use of most animal and animal-derived neuronal models. Recently, in vitro models of VZV latency and reactivation using human neurons derived from stem cells have been established facilitating an understanding of the mechanisms leading to VZV latency and reactivation. From the models, c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase (PI3K) and nerve growth factor (NGF) have all been implicated as potential modulators of VZV latency/reactivation. Additionally, it was shown that the vaccine-strain of VZV is impaired for reactivation. These models may also aid in the generation of prophylactic and therapeutic strategies to treat VZV-associated pathologies. This review summarizes and analyzes the current human neuronal models used to study VZV latency and reactivation, and provides some strategies for their improvement.

scholarly journals Molecular Aspects of Varicella-Zoster Virus Latency

2018 ◽  
Author(s):  
Daniel P. Depledge ◽  
Tomohiko Sadaoka ◽  
Werner J. D. Ouwendijk
Keyword(s):  
Varicella Zoster Virus ◽  
Molecular Mechanisms ◽  
Neurological Complications ◽  
In Vitro Models ◽  
New Era ◽  
Varicella Zoster ◽  
Virus Latency ◽  
Technological Advances ◽  
Molecular Aspects

Primary varicella-zoster virus (VZV) infection causes varicella (chickenpox) and the establishment of a lifelong latent infection in ganglionic neurons. VZV reactivates in about one-third of infected individuals to cause herpes zoster, often accompanied by neurological complications. The restricted host range of VZV and, until recently, the lack of suitable in vitro models to study VZV latency have seriously hampered molecular studies of viral latency. Nevertheless, recent technological advances facilitated a series of exciting studies that resulted in the discovery of a VZV latency-associated transcript (VLT) and have redefined our understanding of VZV latency and factors that initiate reactivation. Together, these findings pave the way for a new era of research that may finally unravel the precise molecular mechanisms that govern latency. In this review, we will summarize the implications of recent discoveries in the VZV latency field from both a virus and host perspective and provide a roadmap for future studies.

scholarly journals Interferon Gamma Prolongs Survival of Varicella-Zoster Virus-Infected Human NeuronsIn Vitro

2015 ◽  
Vol 89 (14) ◽  
pp. 7425-7427 ◽  
Author(s):  
Nicholas L. Baird ◽  
Jacqueline L. Bowlin ◽  
Taylor J. Hotz ◽  
Randall J. Cohrs ◽  
Don Gilden
Keyword(s):  
Varicella Zoster Virus ◽  
Interferon Gamma ◽  
Cytopathic Effect ◽  
Infectious Virus ◽  
Virus Production ◽  
Multiplicity Of Infection ◽  
Varicella Zoster ◽  
Human Neurons

Infection of human neuronsin vitrowith varicella-zoster virus (VZV) at a low multiplicity of infection does not result in a cytopathic effect (CPE) within 14 days postinfection (dpi), despite production of infectious virus. We showed that by 28 dpi a CPE ultimately developed in infected neurons and that interferon gamma inhibited not only the CPE but also VZV DNA accumulation, transcription, and virus production, thereby prolonging the life of VZV-infected neurons.

scholarly journals Human Embryonic Stem Cell-Derived Neurons Are Highly Permissive for Varicella-Zoster Virus Lytic Infection

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Tomohiko Sadaoka ◽  
Cindi L. Schwartz ◽  
Labchan Rajbhandari ◽  
Arun Venkatesan ◽  
Jeffrey I. Cohen
Keyword(s):  
Varicella Zoster Virus ◽  
Cultured Cells ◽  
Human Fibroblasts ◽  
Embryonic Stem ◽  
Vaccine Production ◽  
Varicella Zoster ◽  
Viral Particles ◽  
Human Neurons

ABSTRACTVaricella-zoster virus (VZV) is highly cell associated when grown in culture and has a much higher (4,000- to 20,000-fold increased) particle-to-PFU ratioin vitrothan herpes simplex virus (HSV). In contrast, VZV is highly infectiousin vivoby airborne transmission. Neurons are major targets for VZVin vivo; in neurons, the virus can establish latency and reactivate to produce infectious virus. Using neurons derived from human embryonic stem cells (hESC) and cell-free wild-type (WT) VZV, we demonstrated that neurons are nearly 100 times more permissive for WT VZV infection than very-early-passage human embryonic lung cells or MRC-5 diploid human fibroblasts, the cells used for vaccine production or virus isolation. The peak titers achieved after infection were ∼10-fold higher in human neurons than in MRC-5 cells, and the viral genome copy number-to-PFU ratio for VZV in human neurons was 500, compared with 50,000 for MRC-5 cells. Thus, VZV may not necessarily have a higher particle-to-PFU ratio than other herpesviruses; instead, the cells previously used to propagate virusin vitromay have been suboptimal. Furthermore, based on electron microscopy, neurons infected with VZV produced fewer defective or incomplete viral particles than MRC-5 cells. Our data suggest that neurons derived from hESC may have advantages compared to other cells for studies of VZV pathogenesis, for obtaining stocks of virus with high titers, and for isolating VZV from clinical specimens.IMPORTANCEVaricella-zoster virus (VZV) causes chickenpox and shingles. Cell-free VZV has been difficult to obtain, both forin vitrostudies and for vaccine production. While numerous cells lines have been tested for their ability to produce high titers of VZV, the number of total virus particles relative to the number of viral particles that can form plaques in culture has been reported to be extremely high relative to that in other viruses. We show that VZV grows to much higher titers in human neurons than in other cell typesin vitroand that the number of total virus genomes relative to the number of viral particles that can form plaques in culture is much lower in human neurons than other cultured cells. These findings indicate that human neurons may be useful for studying VZVin vitro, for growing preparations of virus with high titers, and for isolating the virus from human samples.

scholarly journals A unique spliced varicella-zoster virus latency transcript represses expression of the viral transactivator gene 61

2017 ◽  
Author(s):  
Daniel P. Depledge ◽  
Werner J. D. Ouwendijk ◽  
Tomohiko Sadaoka ◽  
Shirley E. Braspenning ◽  
Yasuko Mori ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Functional Characterization ◽  
Skin Lesions ◽  
Reading Frame ◽  
Varicella Zoster ◽  
Viral Transactivator ◽  
Virus Latency ◽  
Latently Infected ◽  
Alternatively Spliced

During primary infection, neurotropic alphaherpesviruses (αHVs) gain access to neurons in sensory and cranial ganglia establishing lifelong latent infection from which they can later reactivate to cause debilitating disease1. For most αHVs, including the best-studied herpes simplex type 1 ( HSV-1), viral latency is characterized by expression of a single or restricted set of transcripts that map antisense to the open reading frame (ORF) homologous to the major HSV immediate early viral transactivator, ICP02. These latency transcripts, either directly or through encoded miRNAs or proteins, repress expression of the ICP0 orthologues3–5. The exception is varicella-zoster virus (VZV), an αHV which infects over 90% of adults and for which neither a canonical latency transcript1,6–8 nor a putative mechanism for repressing lytic transcription during latency have been identified. Here, we describe the discovery and functional characterization of a VZV latency transcript (VLT), that maps antisense to VZV ORF 61 (the VZV ICP0 homologue9,10), and which is consistently expressed in neurons of latently infected human trigeminal ganglia (TG). VLT encodes a protein with late kinetics during lytic VZV infection in vitro and in zoster skin lesions. Whereas multiple alternatively spliced VLT isoforms are expressed during lytic VZV infection, a single unique VLT isoform that specifically suppresses ORF61 gene expression predominates in latently VZV-infected human TG. The discovery of VLT directly unifies the latent VZV transcription program with those of better-characterized αHVs, removing longstanding barriers to understanding VZV latency and paving the way for research into the development of vaccines that do not establish latency or reactivate, and drugs that eradicate latent VZV.

A mouse model for varicella-zoster virus latency

1993 ◽  
Vol 15 (2) ◽  
pp. 141-151 ◽  
Author(s):  
Zofia Wroblewska ◽  
Tibor Valyi-Nagy ◽  
Jessica Otte ◽  
Allan Dillner ◽  
Anita Jackson ◽  
...  
Keyword(s):  
Mouse Model ◽  
Varicella Zoster Virus ◽  
Varicella Zoster ◽  
Virus Latency

Varicella-Zoster Virus Latency in The Nervous System

1984 ◽  
pp. 93-102 ◽  
Author(s):  
Donald H. Gilden ◽  
Abbas Vafai ◽  
Yehuda Shtram ◽  
Yechiel Becker ◽  
Mary Devlin ◽  
...  
Keyword(s):  
Nervous System ◽  
Varicella Zoster Virus ◽  
Varicella Zoster ◽  
Virus Latency

scholarly journals Varicella-Zoster Virus Fc Receptor Component gI Is Phosphorylated on Its Endodomain by a Cyclin-Dependent Kinase

1999 ◽  
Vol 73 (2) ◽  
pp. 1320-1330 ◽  
Author(s):  
Ming Ye ◽  
Karen M. Duus ◽  
Junmin Peng ◽  
David H. Price ◽  
Charles Grose
Keyword(s):  
Fusion Protein ◽  
Varicella Zoster Virus ◽  
Phosphorylation Site ◽  
Cytoplasmic Tail ◽  
Casein Kinase Ii ◽  
Fc Receptor ◽  
Casein Kinase ◽  
Cyclin Dependent Kinase ◽  
Varicella Zoster

Varicella-zoster virus (VZV) glycoprotein gI is a type 1 transmembrane glycoprotein which is one component of the heterodimeric gE:gI Fc receptor complex. Like VZV gE, VZV gI was phosphorylated in both VZV-infected cells and gI-transfected cells. Preliminary studies demonstrated that a serine 343-proline 344 sequence located within the gI cytoplasmic tail was the most likely phosphorylation site. To determine which protein kinase catalyzed the gI phosphorylation event, we constructed a fusion protein, consisting of glutathione-S-transferase (GST) and the gI cytoplasmic tail, called GST-gI-wt. When this fusion protein was used as a substrate for gI phosphorylation in vitro, the results demonstrated that GST-gI-wt fusion protein was phosphorylated by a representative cyclin-dependent kinase (CDK) called P-TEFb, a homologue of CDK1 (cdc2). When serine 343 within the serine-proline phosphorylation site was replaced with an alanine residue, the level of phosphorylation of the gI fusion protein was greatly reduced. Subsequent experiments with individually immunoprecipitated mammalian CDKs revealed that the VZV gI fusion protein was phosphorylated best by CDK1, to a lesser degree by CDK2, and not at all by CDK6. Transient-transfection assays carried out in the presence of the specific CDK inhibitor roscovitine strongly supported the prior results by demonstrating a marked decrease in gI phosphorylation while gI protein expression was unaffected. Finally, the possibility that VZV gI contained a CDK phosphorylation site in its endodomain was of further interest because its partner, gE, contains a casein kinase II phosphorylation site in its endodomain; prior studies have established that CDK1 can phosphorylate casein kinase II.

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