Varicella-Zoster Virus Activates CREB, and Inhibition of the pCREB-p300/CBP Interaction Inhibits Viral ReplicationIn Vitroand Skin PathogenesisIn Vivo

ABSTRACTVaricella-zoster virus (VZV) is an alphaherpesvirus that causes varicella upon primary infection and zoster upon reactivation from latency in sensory ganglion neurons. The replication of herpesviruses requires manipulation of cell signaling pathways. Notably, CREB, a factor involved in the regulation of several cellular processes, is activated upon infection of T cells with VZV. Here, we report that VZV infection also induced CREB phosphorylation in fibroblasts and that XX-650-23, a newly identified inhibitor of the phosphorylated-CREB (pCREB) interaction with p300/CBP, restricted cell-cell spread of VZVin vitro. CREB phosphorylation did not require the viral open reading frame 47 (ORF47) and ORF66 kinases encoded by VZV. Evaluating the biological relevance of these observations during VZV infection of human skin xenografts in the SCID mouse model of VZV pathogenesis showed both that pCREB was upregulated in infected skin and that treatment with XX-650-23 reduced infectious-virus production and limited lesion formation compared to treatment with a vehicle control. Thus, processes of CREB activation and p300/CBP binding are important for VZV skin infection and may be targeted for antiviral drug development.IMPORTANCEVaricella-zoster virus (VZV) is a common pathogen that causes chicken pox and shingles. As with all herpesviruses, the infection is acquired for life, and the virus can periodically reactivate from latency. Although VZV infection is usually benign with few or no deleterious consequences, infection can be life threatening in immunocompromised patients. Otherwise healthy elderly individuals who develop zoster as a consequence of viral reactivation are at risk for postherpetic neuralgia (PHN), a painful and long-lasting complication. Current vaccines use a live attenuated virus that is usually safe but cannot be given to many immunodeficient patients and retains the capacity to establish latency and reactivate, causing zoster. Antiviral drugs are effective against severe VZV infections but have little impact on PHN. A better understanding of virus-host cell interactions is relevant for developing improved therapies to safely interfere with cellular processes that are crucial for VZV pathogenesis.

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

Journal of Virology ◽

10.1128/jvi.00594-15 ◽

2015 ◽

Vol 89 (14) ◽

pp. 7425-7427 ◽

Cited By ~ 10

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.

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Postentry Events Are Responsible for Restriction of Productive Varicella-Zoster Virus Infection in Chinese Hamster Ovary Cells

Journal of Virology ◽

10.1128/jvi.00939-06 ◽

2006 ◽

Vol 80 (21) ◽

pp. 10325-10334 ◽

Cited By ~ 20

Author(s):

Renée L. Finnen ◽

Kara R. Mizokami ◽

Bruce W. Banfield ◽

Guang-Yun Cai ◽

Scott A. Simpson ◽

...

Keyword(s):

Varicella Zoster Virus ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Virus Production ◽

Productive Infection ◽

Progeny Virus ◽

Varicella Zoster Virus Infection ◽

Varicella Zoster ◽

Simplex Virus

ABSTRACT Productive infection of varicella-zoster virus (VZV) in vitro is restricted almost exclusively to cells derived from humans and other primates. We demonstrate that the restriction of productive VZV infection in CHO-K1 cells occurs downstream of virus entry. Entry of VZV into CHO-K1 cells was characterized by utilizing an ICP4/β-galactosidase reporter gene that has been used previously to study herpes simplex virus type 1 entry. Entry of VZV into CHO-K1 cells involved cell surface interactions with heparan sulfate glycosaminoglycans and a cation-independent mannose-6-phosphate receptor. Lysosomotropic agents inhibited the entry of VZV into CHO-K1 cells, consistent with a low-pH-dependent endocytic mechanism of entry. Infection of CHO-K1 cells by VZV resulted in the production of both immediate early and late gene products, indicating that a block to progeny virus production occurs after the initiation of virus gene expression.

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Clinical Features of Varicella-Zoster Virus Infection

Viruses ◽

10.3390/v10110609 ◽

2018 ◽

Vol 10 (11) ◽

pp. 609 ◽

Cited By ~ 41

Author(s):

Peter Kennedy ◽

Anne Gershon

Keyword(s):

Herpes Zoster ◽

Varicella Zoster Virus ◽

Antiviral Drug ◽

Viral Reactivation ◽

Varicella Zoster Virus Infection ◽

Older Individuals ◽

Varicella Zoster ◽

Vesicular Rash ◽

Zoster Sine Herpete ◽

Cranial Neuropathies

Varicella-zoster virus (VZV) is a pathogenic human herpes virus that causes varicella (chickenpox) as a primary infection, following which it becomes latent in peripheral ganglia. Decades later, the virus may reactivate either spontaneously or after a number of triggering factors to cause herpes zoster (shingles). Varicella and its complications are more severe in the immunosuppressed. The most frequent and important complication of VZV reactivation is postherpetic neuralgia, the cause of which is unknown and for which treatment is usually ineffective. Reactivation of VZV may also cause a wide variety of neurological syndromes, the most significant of which is a vasculitis, which is treated with corticosteroids and the antiviral drug acyclovir. Other VZV reactivation complications include an encephalitis, segmental motor weakness and myelopathy, cranial neuropathies, Guillain–Barré syndrome, enteric features, and zoster sine herpete, in which the viral reactivation occurs in the absence of the characteristic dermatomally distributed vesicular rash of herpes zoster. There has also been a recent association of VZV with giant cell arteritis and this interesting finding needs further corroboration. Vaccination is now available for the prevention of both varicella in children and herpes zoster in older individuals.

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Faculty Opinions recommendation of Mannose 6-phosphate receptor dependence of varicella zoster virus infection in vitro and in the epidermis during varicella and zoster.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1023118.266637 ◽

2005 ◽

Author(s):

Jeffrey Cohen

Keyword(s):

Virus Infection ◽

Varicella Zoster Virus ◽

Varicella Zoster Virus Infection ◽

Varicella Zoster ◽

Mannose 6 Phosphate

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Anti-varicella-zoster virus activity of cephalotaxine esters in vitro

The Journal of Microbiology ◽

10.1007/s12275-019-8514-z ◽

2018 ◽

Vol 57 (1) ◽

pp. 74-79 ◽

Cited By ~ 9

Author(s):

Jung-Eun Kim ◽

Yoon-Jae Song

Keyword(s):

Varicella Zoster Virus ◽

Varicella Zoster ◽

Virus Activity

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Combination of azidothymidine (AZT) with (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) leads to inhibition of the in vitro replication of herpes simplex virus type 1 (HSV-1), type 2 (HSV-2) and varicella-zoster virus (VZV) strains that are deficient in thymidine kinase (TK) activity

Antiviral Research ◽

10.1016/0166-3542(95)94883-4 ◽

1995 ◽

Vol 26 (3) ◽

pp. A324

Author(s):

G. Andrei ◽

R. Snoeck ◽

J. Balzarini ◽

E. De Clercq

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Varicella Zoster Virus ◽

Thymidine Kinase ◽

Herpes Simplex Virus Type ◽

Varicella Zoster ◽

Simplex Virus

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Molecular Aspects of Varicella-Zoster Virus Latency

10.20944/preprints201806.0036.v1 ◽

2018 ◽

Cited By ~ 3

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.

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

Journal of Virology ◽

10.1128/jvi.73.2.1320-1330.1999 ◽

1999 ◽

Vol 73 (2) ◽

pp. 1320-1330 ◽

Cited By ~ 34

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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