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 #
5P01AG032958-04
Application #
8231345
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (O1))
Program Officer
Mackiewicz, Miroslaw
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$1,499,976
Indirect Cost
$414,019
Name
University of Colorado Denver
Department
Neurology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Yawn, Barbara P; Wollan, Peter C; Nagel, Maria A et al. (2016) Risk of Stroke and Myocardial Infarction After Herpes Zoster in Older Adults in a US Community Population. Mayo Clin Proc 91:33-44
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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