Compounds that target host cell proteins prevent varicella-zoster virus replication in culture, ex vivo, and in SCID-Hu mice

ABSTRACT During primary infection, varicella-zoster virus (VZV) is spread via lymphocytes to skin, where it induces a rash and establishes latency in sensory ganglia. A live, attenuated varicella vaccine (vOka) was generated by using the VZV Oka strain (pOka), but the molecular basis for vOka attenuation remains unknown. Little is known concerning the effects of wild-type or attenuated VZV on cellular gene regulation in the host cells that are critical for pathogenesis. In this study, transcriptional profiles of primary human T cells and fibroblasts infected with VZV in cell culture were determined by using 40,000-spot human cDNA microarrays. Cellular gene transcription in human skin xenografts in SCID mice that were infected with VZV in vivo was also evaluated. The profiles of cellular gene transcripts that were induced or inhibited in infected human foreskin fibroblasts (HFFs), T cells, and skin in response to pOka and vOka infection were similar. However, significant alterations in cellular gene regulation were observed among the three differentiated human cell types that were examined, suggesting specific differences in the biological consequences of VZV infection related to the target cell. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time reverse transcription-PCR analysis of VZV-infected cells. Interestingly, the transcription of caspase 8 was found to be decreased in infected T cells but not in HFFs or skin, which may signify a tissue-specific antiapoptosis mechanism. The use of microarrays to demonstrate differences in effects on host cell genes in primary, biologically relevant cell types provides background information for experiments to link these various response phenotypes with mechanisms of VZV pathogenesis that are important for the natural course of human infection.

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Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4+ T Cells after Primary Infection

Journal of Virology ◽

10.1128/jvi.00564-06 ◽

2006 ◽

Vol 80 (19) ◽

pp. 9772-9778 ◽

Cited By ~ 27

Author(s):

Louise Jones ◽

Antony P. Black ◽

Gathsaurie N. Malavige ◽

Graham S. Ogg

Keyword(s):

T Cells ◽

Varicella Zoster Virus ◽

Peripheral Blood ◽

Primary Infection ◽

Ex Vivo ◽

High Frequencies ◽

Varicella Zoster ◽

Early Protein ◽

Orf4 Protein ◽

Ifn Γ

ABSTRACT Open reading frame 4 (ORF4) of varicella-zoster virus (VZV) encodes an immediate-early protein that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication, but there are no data addressing the existence of potential ORF4 protein-specific CD4+ T cells. We tested the hypothesis that VZV ORF4 protein-specific CD4+ T cells could be identified and characterized within the peripheral blood of healthy immune donors following primary infection. Gamma interferon (IFN-γ) immunosorbent assays were used to screen peripheral blood mononuclear cells obtained from healthy seropositive donors for responses to overlapping ORF4 peptides, viral lysate, and live vaccine. High frequencies of ORF4 protein-specific T cells were detected ex vivo in individuals up to 52 years after primary infection. Several immunogenic regions of the ORF4 protein were identified, including a commonly recognized epitope which was restricted through HLA-DRB1*07. Total ORF4 protein-specific responses comprised 19.7% and 20.7% of the total lysate and vaccine responses, respectively, and were dominated by CD4+ T cells. Indeed, CD4+ T cells were found to dominate the overall virus-specific IFN-γ cellular immune response both ex vivo and after expansion in vitro. In summary, we have identified an ORF4 protein as a novel target antigen for persistent VZV-specific CD4+ T cells, with implications for disease pathogenesis and future vaccine development.

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Replication of Varicella-Zoster Virus in Human Skin Organ Culture

Journal of Virology ◽

10.1128/jvi.79.17.11501-11506.2005 ◽

2005 ◽

Vol 79 (17) ◽

pp. 11501-11506 ◽

Cited By ~ 26

Author(s):

Shannon L. Taylor ◽

Jennifer F. Moffat

Keyword(s):

Organ Culture ◽

Varicella Zoster Virus ◽

Ex Vivo ◽

Plaque Assay ◽

Rodent Models ◽

Fetal Skin ◽

Varicella Zoster ◽

Transmission Electron ◽

Models Of Disease ◽

Skin Organ Culture

ABSTRACT Varicella-zoster virus (VZV) infection is restricted to humans, which hinders studies of its pathogenesis in rodent models of disease. To facilitate the study of VZV skin tropism, we developed an ex vivo system using human fetal skin organ culture (SOC). VZV replication was analyzed by plaque assay, transmission electron microscopy, and histology. The yield of infectious VZV from SOC increased ∼100-fold over 6 days, virions were abundant, and lesions developed that contained VZV antigens and resembled varicella and zoster lesions. The SOC system for VZV replication has applications for testing virus mutants and antiviral drugs.

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Resveratrol inhibition of varicella-zoster virus replication in vitro

Antiviral Research ◽

10.1016/j.antiviral.2006.07.004 ◽

2006 ◽

Vol 72 (3) ◽

pp. 171-177 ◽

Cited By ~ 68

Author(s):

John J. Docherty ◽

Thomas J. Sweet ◽

Erin Bailey ◽

Seth A. Faith ◽

Tristan Booth

Keyword(s):

Varicella Zoster Virus ◽

Virus Replication ◽

Varicella Zoster

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3D Reconstruction of Varicella-Zoster Virus Infected Host Cell Nuclei and PML Cages by Serial Section Array-SEM and TEM Tomography.

Microscopy and Microanalysis ◽

10.1017/s1431927612002735 ◽

2012 ◽

Vol 18 (S2) ◽

pp. 176-177

Author(s):

M. Reichelt ◽

L. Joubert ◽

J. Perrino ◽

A. Ko ◽

I. Phanwar ◽

...

Keyword(s):

3D Reconstruction ◽

Varicella Zoster Virus ◽

Host Cell ◽

Serial Section ◽

Infected Host ◽

Cell Nuclei ◽

Varicella Zoster ◽

Infected Host Cell ◽

Sem And Tem

Extended abstract of a paper presented at Microscopy and Microanalysis 2012 in Phoenix, Arizona, USA, July 29 – August 2, 2012.

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Honeysuckle-derived microRNA2911 directly inhibits varicella-zoster virus replication by targeting IE62 gene

Journal of NeuroVirology ◽

10.1007/s13365-019-00741-2 ◽

2019 ◽

Vol 25 (4) ◽

pp. 457-463 ◽

Cited By ~ 2

Author(s):

Ying Huang ◽

Huabo Liu ◽

Xinlei Sun ◽

Meng Ding ◽

Gaojian Tao ◽

...

Keyword(s):

Varicella Zoster Virus ◽

Virus Replication ◽

Varicella Zoster

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Components of Nuclear Domain 10 Bodies Regulate Varicella-Zoster Virus Replication

Journal of Virology ◽

10.1128/jvi.00021-09 ◽

2009 ◽

Vol 83 (9) ◽

pp. 4262-4274 ◽

Cited By ~ 35

Author(s):

Christos A. Kyratsous ◽

Saul J. Silverstein

Keyword(s):

Varicella Zoster Virus ◽

Virus Replication ◽

Control Cell ◽

Host Cells ◽

Virus Protein ◽

Protein Accumulation ◽

Dna Virus ◽

Varicella Zoster ◽

Early Protein ◽

Nuclear Domains

ABSTRACT PML, Sp100, and Daxx are proteins that normally reside within nuclear domains 10 (ND10s). They associate with DNA virus genomes and repress the very early stages of the DNA virus replication cycle. Virus-encoded proteins counteract this innate antiviral response. ICP0, a herpes simplex virus (HSV) immediate-early protein, is necessary and sufficient to dissociate ND10s and target their two major components, PML and Sp100, for proteasomal degradation. In this report, we show that ORF61p, the varicella-zoster virus (VZV) ortholog of ICP0, does not degrade PML and alters Sp100 levels only slightly. Furthermore, we demonstrate that other virus proteins cannot substitute for this lack of function during infection. By using short interfering RNAs, we depleted PML, Sp100, and Daxx and studied their roles in plaquing efficiency, virus protein accumulation, infectious-center titer, and virus spread. The results of these studies show that components of ND10s can accelerate VZV replication but do not ultimately control cell-associated virus titers. We conclude that while both ICP0 and ORF61p activate virus gene expression, they modulate host innate repression mechanisms in two different ways. As a result, HSV and VZV commandeer their host cells by distinct mechanisms to ensure their replication and spread.

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