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
Como, Christina N; Pearce, Catherine M; Cohrs, Randall J et al. (2018) Interleukin-6 and type 1 interferons inhibit varicella zoster virus replication in human neurons. Virology 522:13-18
Mahalingam, Ravi; Kaufer, Benedikt B; Ouwendijk, Werner J D et al. (2018) Attenuation of Simian Varicella Virus Infection by Enhanced Green Fluorescent Protein in Rhesus Macaques. J Virol 92:
Cohrs, Randall J; Badani, Hussain; Baird, Nicholas L et al. (2017) Induction of varicella zoster virus DNA replication in dissociated human trigeminal ganglia. J Neurovirol 23:152-157
Cohrs, Randall J; Lee, Katherine S; Beach, Addilynn et al. (2017) Targeted Genome Sequencing Reveals Varicella-Zoster Virus Open Reading Frame 12 Deletion. J Virol 91:
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Gilden, Don; White, Teresa; Khmeleva, Nelly et al. (2016) Blinded search for varicella zoster virus in giant cell arteritis (GCA)-positive and GCA-negative temporal arteries. J Neurol Sci 364:141-3

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