Varicella zoster virus (VZV) causes childhood varicella (chickenpox), becomes latent in ganglionic neurons at all levels of the neuraxis and reactivates decades later to cause zoster (shingles) and postherpetic neuralgia (PHN), especially in the elderly. Although a zoster vaccine is available, even if every adult in the U.S. >60 years were vaccinated, there would still be -500,000 zoster cases annually, about 200,000 of whom will experience PHN, stroke, blindness or myelopathy caused by VZV reactivation. An alternative to vaccination is prevention of virus reactivation based on an in-depth understanding of the physical state of viral nucleic acid and gene expression during latency and their changes during reactivation. We and others have shown that VZV IE63, the immediate early (IE)protein encoded by open reading frame 63, is a consistent hallmark of VZV latency. Based on the fact that IE63, a predominantly nuclear phosphoprotein during productive infection, is located exclusively in the cytoplasm of latently- infected neurons where its phosphorylation state is unknown, we hypothesize that translocation of IE63 from the cytoplasm to the nucleus results in altered IE63 function and initiation of virus reactivation. We will test this hypothesis by identifying cytoplasmic and nuclear forms of IE63 and their functions in neuronal and non-neuronal cells in culture (Aim1), the cellular location of IE63 in human ganglia during virus reactivation (Aim2), and the pattern of VZV gene transcription and their epigenetic regulation during reactivation in explanted human trigeminal ganglia (Aim3). These studies will provide the first comprehensive picture of VZV reactivation in humans. We are uniquely qualified to carry out these studies since we have a continuous supply of human ganglia obtained at autopsy, have shown that ganglia from more than 90% of humans are latently infected with VZV,that VZV reactivation occurs after explantation, and that optimized GeXP technology detects low-abundance VZV gene transcripts. Further, we have constructed recombinant mouse anti-IE63 antibodies that recognize nuclear or cytoplasmic forms of IE63. Our in-depth analysis of the mechanism of VZV reactivation in human TG will identify new targets for therapeutic intervention to prevent virus reactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG032958-05
Application #
8434125
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$315,734
Indirect Cost
$109,372
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:
Nagel, Maria A; Jones, Dallas; Wyborny, Ann (2017) Varicella zoster virus vasculopathy: The expanding clinical spectrum and pathogenesis. J Neuroimmunol 308:112-117
Ouwendijk, Werner J D; van Veen, Suzanne; Mahalingam, Ravi et al. (2017) Simian varicella virus inhibits the interferon gamma signalling pathway. J Gen Virol :
Jones, Dallas; Alvarez, Enrique; Selva, Sean et al. (2016) Proinflammatory cytokines and matrix metalloproteinases in CSF of patients with VZV vasculopathy. Neurol Neuroimmunol Neuroinflamm 3:e246
Gilden, Don; White, Teresa; Boyer, Philip J et al. (2016) Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta. J Infect Dis 213:1866-71
Keller, Amy C; Badani, Hussain; McClatchey, P Mason et al. (2016) Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology. J Neurovirol 22:674-682
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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