scholarly journals Attenuation of the Vaccine Oka Strain of Varicella-Zoster Virus and Role of Glycoprotein C in Alphaherpesvirus Virulence Demonstrated in the SCID-hu Mouse

1998 ◽  
Vol 72 (2) ◽  
pp. 965-974 ◽  
Author(s):  
Jennifer F. Moffat ◽  
Leigh Zerboni ◽  
Paul R. Kinchington ◽  
Charles Grose ◽  
Hideto Kaneshima ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Varicella Zoster Virus ◽  
Human Skin ◽  
Critical Role ◽  
Varicella Vaccine ◽  
Varicella Zoster ◽  
Glycoprotein C ◽  
Low Passage ◽  
Hsv 1

ABSTRACT The SCID-hu mouse implanted with human fetal tissue is a novel model for investigating human viral pathogenesis. Infection of human skin implants was used to investigate the basis for the clinical attenuation of the varicella-zoster virus (VZV) strain, V-Oka, from which the newly licensed vaccine is made. The pathogenicity of V-Oka was compared with that of its parent, P-Oka, another low-passage clinical isolate, strain Schenke (VZV-S), and VZV-Ellen, a standard laboratory strain. The role of glycoprotein C (gC) in infectivity for human skin was assessed by using gC-negative mutants of V-Oka and VZV-Ellen. Whereas all of these VZV strains replicated well in tissue culture, only low-passage clinical isolates were fully virulent in skin, as shown by infectious virus yields and analysis of implant tissues for VZV DNA and viral protein synthesis. The infectivity of V-Oka in skin was impaired compared to that of P-Oka, providing the first evidence of a virologic basis for the clinical attenuation of V-Oka. The infectivity of V-Oka was further diminished in the absence of gC expression. All strains except gC-Ellen retained some capacity to replicate in human skin, but cell-free virus was recovered only from implants infected with P-Oka or VZV-S. Although VZV is closely related to herpes simplex virus type 1 (HSV-1) genetically, experiments in the SCID-hu model revealed differences in tropism for human cells that correlated with differences in VZV and HSV-1 disease. VZV caused extensive infection of epidermal and dermal skin cells, while HSV-1 produced small, superficial lesions restricted to the epidermis. As in VZV, gC expression was a determinant for viral replication in skin. VZV infects human CD4+ and CD8+ T cells in thymus/liver implants, but HSV-1 was detected only in epithelial cells, with no evidence of lymphotropism. These SCID-hu mouse experiments show that the clinical attenuation of the varicella vaccine can be attributed to decreased replication of V-Oka in skin and that tissue culture passage alone reduces the ability of VZV to infect human skin in vivo. Furthermore, gC, which is dispensable for replication in tissue culture, plays a critical role in the virulence of the human alphaherpesviruses VZV and HSV-1 for human skin.

scholarly journals Varicella-Zoster Virus Proteins in Skin Lesions: Implications for a Novel Role of ORF29p in Chickenpox

2000 ◽  
Vol 74 (4) ◽  
pp. 2005-2010 ◽  
Author(s):  
Paula W. Annunziato ◽  
Octavian Lungu ◽  
Christos Panagiotidis ◽  
Jing H. Zhang ◽  
David N. Silvers ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Skin Biopsy ◽  
Varicella Zoster Virus ◽  
Nuclear Protein ◽  
Cell Types ◽  
Skin Lesions ◽  
Varicella Zoster ◽  
Human Neurons ◽  
Virus Proteins

ABSTRACT Skin biopsy samples from varicella-zoster virus (VZV)-infected patients examined by immunohistochemistry demonstrated VZV replication in nonepithelial cell types. ORF29p, a nonstructural nuclear protein, was found in nerves of two of six patients with chickenpox. In tissue culture, ORF29p was secreted by VZV-infected fibroblasts. Extracellular ORF29p can be taken up through endocytosis by human neurons, implying a novel role for this protein in pathogenesis.

scholarly journals Discordant varicella-zoster virus glycoprotein C expression and localization between cultured cells and human skin vesicles

Virology ◽  
2008 ◽  
Vol 382 (2) ◽  
pp. 171-181 ◽  
Author(s):  
Johnathan Storlie ◽  
John E. Carpenter ◽  
Wallen Jackson ◽  
Charles Grose
Keyword(s):  
Varicella Zoster Virus ◽  
Human Skin ◽  
Cultured Cells ◽  
Varicella Zoster ◽  
Glycoprotein C ◽  
Virus Glycoprotein

Varicella-Zoster Virus (Varicella and Shingles)

2021 ◽  
Author(s):  
Anne Gershon
Keyword(s):  
Varicella Zoster Virus ◽  
Varicella Vaccine ◽  
The United States ◽  
Primary Immune Response ◽  
Wild Type Virus ◽  
High Dose ◽  
Healthy Children ◽  
Zoster Vaccine ◽  
Live Attenuated Vaccine ◽  
Varicella Zoster

A live attenuated vaccine against varicella (later also used to prevent zoster) was developed in 1974 by Takahashi and colleagues. Varicella vaccine was licensed for universal immunization of healthy children in the United States in 1995. It is also now used for this purpose in at least 15 additional countries all over the world. Varicella is disappearing in the US. Varicella vaccine has proven extremely safe and side effects are unusual, mild, and less serious than varicella or its complications. 85% of children are protected completely after 1 dose; the 15% who develop varicella despite immunization usually (but not always) have mild infections. These 15%, however, can transmit the wild type virus to others. Therefore, for optimal effect, 2 doses are required, mostly to address children who did not have an optimal primary immune response after the first dose. Waning immunity does not seem to pose a serious problem, but surveillance of vaccinees is continuing. It was demonstrated in 2005 that at a high dose of vaccine – 15 times higher than that used for prevention of varicella in children - zoster in adults can also be safely prevented. The live attenuated zoster vaccine is effective in approximately 50% of healthy individuals over age 60 who have had varicella in the past, and therefore have latent infection with varicella-zoster virus. It is given as one dose, but its effect runs out about 8 years after vaccination. In 2017, a new vaccine against zoster was also introduced. This is a subunit vaccine which does not contain contagious virus. It is even more effective than the older zoster vaccine and is over 95% effective in adults 50–≥70 years of age in preventing zoster and post herpetic neuralgia.

scholarly journals Varicella-Zoster Virus IE63, a Major Viral Latency Protein, Is Required To Inhibit the Alpha Interferon-Induced Antiviral Response

2007 ◽  
Vol 81 (15) ◽  
pp. 7844-7851 ◽  
Author(s):  
Aruna P. N. Ambagala ◽  
Jeffrey I. Cohen
Keyword(s):  
Varicella Zoster Virus ◽  
Melanoma Cells ◽  
Alpha Interferon ◽  
Parental Virus ◽  
Initiation Factor ◽  
Viral Gene ◽  
Α Subunit ◽  
Varicella Zoster ◽  
In Cells ◽  
Hsv 1

ABSTRACT Varicella-zoster virus (VZV) open reading frame 63 (ORF63) is the most abundant transcript expressed during latency in human sensory ganglia. VZV with ORF63 deleted is impaired for replication in melanoma cells and fibroblasts and for latency in rodents. We found that replication of the ORF63 deletion mutant is fully complemented in U2OS cells, which have been shown to complement the growth of herpes simplex virus type 1 (HSV-1) ICP0 mutants. Since HSV-1 ICP0 mutants are hypersensitive to alpha interferon (IFN-α), we examined the effect of IFN-α on VZV replication. Replication of the ORF63 mutant in melanoma cells was severely inhibited in the presence of IFN-α, in contrast to other VZV mutants that were similarly impaired for replication or to parental virus. The VZV ORF63 mutant was not hypersensitive to IFN-γ. IFN-α inhibited viral-gene expression in cells infected with the ORF63 mutant at a posttranscriptional level. Since IFN-α stimulates gene products that can phosphorylate the α subunit of eukaryotic initiation factor 2 (eIF-2α) and inhibit translation, we determined whether cells infected with the ORF63 mutant had increased phosphorylation of eIF-2α compared with cells infected with parental virus. While phosphorylated eIF-2α was undetectable in uninfected cells or cells infected with parental virus, it was present in cells infected with the ORF63 mutant. Conversely, expression of IE63 (encoded by ORF63) in the absence of other viral proteins inhibited phosphorylation of eIF-2α. Since IFN-α has been shown to limit VZV replication in human skin xenografts, the ability of VZV IE63 to block the effects of the cytokine may play a critical role in VZV pathogenesis.

Nectin-1 is an entry mediator for VZV infection of human neurons

2021 ◽  
Author(s):  
Labchan Rajbhandari ◽  
Priya Shukla ◽  
Balaji Jagdish ◽  
Abby Mandalla ◽  
Qingxue Li ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Mammalian Cells ◽  
Primary Infection ◽  
Transcriptional Profiling ◽  
Varicella Vaccine ◽  
Ectopic Expression ◽  
Neuronal Model ◽  
Morbidity And Mortality ◽  
Varicella Zoster ◽  
Human Neurons

Varicella zoster virus (VZV) maintains lifelong latency in neurons following initial infection and can subsequently be reactivated to result in herpes zoster or severe neurological manifestations such as encephalitis. Mechanisms of VZV neuropathogenesis have been challenging to study due to the strict human tropism of the virus. While neuronal entry mediators of other herpesviruses, including herpes simplex virus, have been identified, little is known regarding how VZV enters neurons. Here, we utilize a human stem cell based neuronal model to characterize cellular factors that mediate entry. Through transcriptional profiling of infected cells, we identify the cell adhesion molecule nectin-1 as a candidate mediator of VZV entry. Nectin-1 is highly expressed in the cell bodies and axons of neurons. Either knockdown of endogenous nectin-1 or incubation with soluble forms of nectin-1 produced in mammalian cells results in a marked decrease in infectivity of neurons. Notably, while addition of soluble nectin-1 during viral infection inhibits infectivity, addition after infection has no effect on infectivity. Ectopic expression of human nectin-1 in a cell line resistant to productive VZV infection confers susceptibility to infection. In summary, we have identified nectin-1 as a neuronal entry mediator of VZV. IMPORTANCE Varicella zoster virus (VZV) causes chickenpox, gains access to neurons during primary infection where it resides lifelong, and can later be reactivated. Reactivation is associated with shingles and postherpetic neuralgia, as well as with severe neurologic complications including vasculitis and encephalitis. Although the varicella vaccine substantially decreases morbidity and mortality associated with primary infection, the vaccine cannot prevent development of neuronal latency and vaccinated populations are still at risk for reactivation. Furthermore, immunocompromised individuals are at higher risk for VZV reactivation and associated complications. Little is known regarding how VZV enters neurons. Here, we identify nectin-1 as an entry mediator of VZV in human neurons. Identification of nectin-1 as a neuronal VZV entry mediator could lead to improved treatments and preventative measures to reduce VZV related morbidity and mortality.

Long-Term Protective Immunity of Recipients of the OKA Strain of Live Varicella Vaccine

PEDIATRICS ◽  
1985 ◽  
Vol 75 (4) ◽  
pp. 667-671 ◽  
Author(s):  
Yoshizo Asano ◽  
Takao Nagai ◽  
Takao Miyata ◽  
Takehiko Yazaki ◽  
Shigemitsu Ito ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Skin Reaction ◽  
Protective Immunity ◽  
Geometric Mean ◽  
Varicella Vaccine ◽  
Geometric Mean Titer ◽  
Positive Skin ◽  
Varicella Zoster ◽  
Mean Diameter

In spite of close contacts with patients who had varicella, 101 of 106 (95%) healthy and sick children (142 of 147 (97%) exposures of these children) who had received the OKA strain of live varicella vaccine 7 to 10 years earlier were protected against the disease completely. Among them, 37 of 38 (97%) vaccine recipients who received immunologic testing had varicella-zoster virus (VZV) antibodies tested by fluorescent antibody to membrane antigen method with a geometric mean titer of 1:9.3, and 37 of the 38 (97%) showed positive skin reaction to varicella-zoster virus antigen with erythema (mean diameter 13.4 mm). These findings were compared with those for 29 children who had contracted typical varicella 7 to 10 years earlier, whose seropositive rate was 100% with a geometric mean titer of 1:10.5, and 97% of whom (28/29) had positive skin reaction with mean diameter of 12.9 mm. These results indicate that the vaccine-induced protective immunity persists for approximately one decade and is almost equal to the long-term immunity following natural infection.

scholarly journals A Novel Human Skin Tissue Model To Study Varicella-Zoster Virus and Human Cytomegalovirus

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Megan G. Lloyd ◽  
Nicholas A. Smith ◽  
Michael Tighe ◽  
Kelsey L. Travis ◽  
Dongmei Liu ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Human Skin ◽  
Mouse Models ◽  
Human Cytomegalovirus ◽  
Fetal Tissue ◽  
Target Cells ◽  
Varicella Zoster ◽  
Adult Human ◽  
Infected Cells ◽  
Adult Human Skin

ABSTRACT The herpesviruses varicella-zoster virus (VZV) and human cytomegalovirus (HCMV) are endemic to humans. VZV causes varicella (chicken pox) and herpes zoster (shingles), while HCMV causes serious disease in immunocompromised patients and neonates. More effective, less toxic antivirals are needed, necessitating better models to study these viruses and evaluate antivirals. Previously, VZV and HCMV models used fetal tissue; here, we developed an adult human skin model to study VZV and HCMV in culture and in vivo. While VZV is known to grow in skin, it was unknown whether skin could support an HCMV infection. We used TB40/E HCMV and POka VZV strains to evaluate virus tropism in skin organ culture (SOC) and skin xenograft mouse models. Adult human skin from reduction mammoplasties was prepared for culture on NetWells or mouse implantation. In SOC, VZV infected the epidermis and HCMV infected the dermis. Specifically, HCMV infected fibroblasts, endothelial cells, and hematopoietic cells, with some infected cells able to transfer infection. VZV and HCMV mouse models were developed by subcutaneous transplantation of skin into SCID/beige or athymic nude mice at 2 independent sites. Viruses were inoculated directly into one xenograft, and widespread infection was observed for VZV and HCMV. Notably, we detected VZV- and HCMV-infected cells in the contralateral, uninoculated xenografts, suggesting dissemination from infected xenografts occurred. For the first time, we showed HCMV successfully grows in adult human skin, as does VZV. Thus, this novel system may provide a much-needed preclinical small-animal model for HCMV and VZV and, potentially, other human-restricted viruses. IMPORTANCE Varicella-zoster virus and human cytomegalovirus infect a majority of the global population. While they often cause mild disease, serious illness and complications can arise. Unfortunately, there are few effective drugs to treat these viruses, and many are toxic. To complicate this, these viruses are restricted to replication in human cells and tissues, making them difficult to study in traditional animal models. Current models rely heavily on fetal tissues, can be prohibitively expensive, and are often complicated to generate. While fetal tissue models provide helpful insights, it is necessary to study human viruses in human tissue systems to fully understand these viruses and adequately evaluate novel antivirals. Adult human skin is an appropriate model for these viruses because many target cells are present, including basal keratinocytes, fibroblasts, dendritic cells, and lymphocytes. Skin models, in culture and xenografts in immunodeficient mice, have potential for research on viral pathogenesis, tissue tropism, dissemination, and therapy.

scholarly journals Epigenetic Regulation of Varicella-Zoster Virus Open Reading Frames 62 and 63 in Latently Infected Human Trigeminal Ganglia

2006 ◽  
Vol 80 (10) ◽  
pp. 4921-4926 ◽  
Author(s):  
Lee Gary ◽  
Donald H. Gilden ◽  
Randall J. Cohrs
Keyword(s):  
Varicella Zoster Virus ◽  
Chromatin Immunoprecipitation ◽  
Latent Infection ◽  
Open Reading Frames ◽  
Trigeminal Ganglia ◽  
Varicella Zoster ◽  
Glycoprotein C ◽  
Latently Infected ◽  
Human Chromosome 4 ◽  
Reading Frames

ABSTRACT Open reading frames (ORFs) 21, 29, 62, 63, and 66 of varicella-zoster virus (VZV) are transcribed during latency in human ganglia. ORF 63 is the most frequently expressed gene, and ORF 62 encodes a transcriptional activator. The mechanisms regulating the expression of these genes are not well understood, although analyses of other alphaherpesviruses indicate a role for chromatin in virus gene regulation during latent infection. Using chromatin immunoprecipitation (ChIP) assays to analyze the euchromatic state of ORFs 62 and 63 compared to the centromere from human chromosome 4 (heterochromatic) and the human glyceraldehyde-3-phosphate dehydrogenase promoter (euchromatic), we show that the promoters of ORFs 62 and 63 are associated with the histone protein H3K9(Ac) and thus maintained in a euchromatic state during latency. Conversely, the promoters of ORF 36 (thymidine kinase) and ORF 14 (glycoprotein C), genes expressed during lytic but not latent infection, were not enriched in the fraction of latently infected ganglia that bound to anti-H3K9(Ac) antibody. A ChIP assay using productively infected MeWo cells revealed that VZV ORFs 62, 63, 36, and 14 are all euchromatic. Together, these data indicate that the expression of the two latency-related VZV genes, ORFs 62 and 63, is regulated epigenetically through chromatin structure.

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