The goal of this program project is to understand the relationship between the latent state of the highly neurotropic varicella zoster virus (VZV) in human ganglia and the development of acute and chronic neurologic disease produced by virus reactivation. The program project contains an administrative core, a scientific core and 3 scientific projects. Primary infection by varicella zoster virus (VZV) usually causes varicella (chickenpox), after which virus becomes latent in human ganglionic neurons along the entire neuraxis. With aging, a declining cell-mediated immunity to VZV leads to virus reactivation, manifesting as herpes zoster (shingles) characterized by pain and rash restricted to 1-3 dermatomes. The incidence and severity of zoster is also high in transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), as well as paralysis, blindness and stroke. Currently, ~1,000,000 Americans develop zoster annually. Oka VZV vaccine reduces the incidence of zoster by 50%, but even if every American over age 60 was vaccinated, >500,000 cases of zoster would still occur every year. This program project is focused exclusively on the molecular pathogenesis of primary VZV infection, latency and reactivation. Project 1 studies inhibition of apoptosis by both viral and cellular proteins during VZV infection of neurons that results in neuronal survival and viral latency. Project 2 studies molecular mechanisms of VZV latency and reactivation in ganglia, focusing on VZV IE63, the protein product of the most prevalent and abundant transcript identified in latently infected human ganglia, and whose translocation from the cytoplasm to the nucleus may result in altered IE63 function and induction of virus reactivation. Project 3 studies the immunobiology of varicella in an animal model, focusing on identification of host cell types and their role in transport and establishment of varicella infection in skin and ganglia during primary infection and cytokine expression and virus-specific T cells in varicella reactivation. A comprehensive knowledge of the physical state of latent and reactivated VZV and simian varicella virus (SVV) will provide the rational underpinning for strategies to prevent the cascade of events leading to human VZV reactivation, a cause of serious neurologic disease, particularly in the rapidly increasing elderly and immunocompromised populations. This proposal melds the skills and strategies of investigators with expertise in clinical neurology, virology, molecular and cell biology and clinical investigation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG032958-04S1
Application #
8458407
Study Section
Program Officer
Mackiewicz, Miroslaw
Project Start
2012-05-01
Project End
2013-02-28
Budget Start
2012-08-15
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$97,204
Indirect Cost
$33,464
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
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:
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 :
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:
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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