VZV reactivation is a serious problem in the elderly and immunocompromised populations. Because VZV becomes latent after naturally occurring primary infection (varicella), and in children who are vaccinated to prevent varicella, reactivation in the elderly is a universal problem. VZV reactivation leads to zoster, which is often complicated by chronic pain (postherpetic neuralgia), paralysis and incontinence (myelopathy), headache and cognitive impairment (meningoencephalitis) and sometimes blindness (retinitis) and stroke (vasculopathy). Finding targets for therapeutic intervention to prevent VZV reactivation requires understanding the mechanisms by which virus genes are transcribed from the latent, repressed virus genome. Our recent finding that VZV transcription undergoes a profound change as the virus transitions from latency to reactivation forms the basis of our hypothesis that VZV reactivation is initially dependent on epigenetic modifications of latent virus DNA and subsequently dependent on functions provided by the cell or induced by the virus. To test our hypothesis, we will exploit our continuous supply of adult human ganglia latently infected with VZV, our optimized protocol to dissociate ganglia while maintaining neuronal viability, and our extremely sensitive multiplex-based PCR assay that detects the entire VZV transcriptome in human ganglia.
Aim 1 will determine the events regulating VZV gene transcription as reactivation progresses from latency (transcription of a few genes) to initiation of reactivation (random transcription of many genes). Increased VZV gene transcription in dissociated, latently infected human ganglia associated with treatments designed to modify proteins bound to the virus genome will help to identify the mechanisms through which the silenced virus genome undergoes generalized deregulation of transcription.
Aim 2 will identify cell pathways or virus genes that potentiate VZV DNA replication and release of infectious virus from latently infected human neurons. VZV DNA replication (qPCR) and virus production (plaque assay on indicator cells) will be determined in latently infected adult human neurons in response to modification of cellular apoptosis, NGF, innate and adaptive immune signaling pathways and expression of VZV immediate-early proteins (via replication deficient, recombinant adenovirus vectors). Together, our analyses will determine the mechanisms by which latent VZV reactivates from adult human neurons in an experimental system that is easily modified to identify ideal therapeutic targets to inhibit virus reactivation, the cause of zoster and its serious attendant neurologic and ocular complications.

Public Health Relevance

Our studies will test the hypothesis that VZV reactivation involves generalized deregulation of virus gene transcription followed by activity of factors contributed by the cell or induced by VZV. This project unites seemingly disparate findings observed during latency and reactivation among human neurotropic alphaherpesviruses into a single testable hypothesis that will translate to candidate targets for therapeutic interventions to reduce, if not eliminate, severe disease, primarily in the elderly caused by VZV reactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG032958-06
Application #
8636735
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (02))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$333,898
Indirect Cost
$118,190
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Henderson, Heather H; Timberlake, Kensey B; Austin, Zoe A et al. (2016) Occupancy of RNA Polymerase II Phosphorylated on Serine 5 (RNAP S5P) and RNAP S2P on Varicella-Zoster Virus Genes 9, 51, and 66 Is Independent of Transcript Abundance and Polymerase Location within the Gene. J Virol 90:1231-43
Ouwendijk, Werner J D; Getu, Sarah; Mahalingam, Ravi et al. (2016) Characterization of the immune response in ganglia after primary simian varicella virus infection. J Neurovirol 22:376-88
Nagel, Maria A; Gilden, Don (2016) Developments in Varicella Zoster Virus Vasculopathy. Curr Neurol Neurosci Rep 16:12
Nagel, Maria A; Burns, Ted M; Gilden, Don (2016) SUNCT headaches after ipsilateral ophthalmic-distribution zoster. J Neurol Sci 366:207-8
Gilden, Don; White, Teresa; Khmeleva, Nelly et al. (2016) VZV in biopsy-positive and -negative giant cell arteritis: Analysis of 100+ temporal arteries. Neurol Neuroimmunol Neuroinflamm 3:e216
Jones, Dallas; Blackmon, Anna; Neff, C Preston et al. (2016) Varicella-Zoster Virus Downregulates Programmed Death Ligand 1 and Major Histocompatibility Complex Class I in Human Brain Vascular Adventitial Fibroblasts, Perineurial Cells, and Lung Fibroblasts. J Virol 90:10527-10534
Gilden, Don; Grose, Charles; White, Teresa et al. (2016) Successful antiviral treatment after 6years of chronic progressive neurological disease attributed to VZV brain infection. J Neurol Sci 368:240-2
Gilden, Don; Nagel, Maria A (2016) Varicella zoster virus triggers the immunopathology of giant cell arteritis. Curr Opin Rheumatol 28:376-82
Amlie-Lefond, Catherine; Gilden, Don (2016) Varicella Zoster Virus: A Common Cause of Stroke in Children and Adults. J Stroke Cerebrovasc Dis 25:1561-9

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