The goal of this program project (PPG) is to prevent serious neurological disease in the elderly caused by reactivation of the ubiquitous highly neurotropic varicella zoster virus (VZV). The PPG contains 3 scientific projects and supportive administrative and scientific cores. Primary infection by varicella zoster virus (VZV) usually causes varicella, after which virus becomes latent in 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 increased in organ transplant recipients and patients with cancer or AIDS. Zoster is frequently complicated by chronic pain (postherpetic neuralgia), 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 would still occur every year. This PPG will: determine the emerging role of multifocal VZV vasculopathy as an important cause of vision loss and headaches in the elderly, examine mechanisms by which VZV exits latency to cause disease and identify key virus-host interactions involved in immunity and spread of infection. Project 1, an exciting new translational project, will identify clinical, laboratory and pathological features of a form of multifocal VZV vasculopathy that mimics giant cell arteritis (GCA), a cause of vision loss and headache in the elderly, findings that are likely to shift the current clinical practice paradigm. Project 2 tests the hypothesis that VZV reactivation initially involves generalized deregulation of latent gene transcription followed by conditions conducive to virus DNA replication and release of infectious virus. Project 3 uses an animal model to determine critical virus-host immune cell interactions that contribute to viral pathogenesis. The combined studies will provide valuable clinical, laboratory and pathological data needed to diagnose and treat a form of multifocal VZV vasculopathy that mimics giant cell arteritis and will provide the needed molecular groundwork for efforts to prevent the cascade of events leading to 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 MDs, PhDs and DVMs with expertise in clinical neurology, molecular virology and immunology.

Public Health Relevance

Varicella zoster virus (VZV) is a ubiquitous highly neurotropic exclusively human alphaherpesvirus that causes significant morbidity and mortality. The goal of this program project is to expand the spectrum of disease caused by VZV and determine mechanisms of latency and pathogenesis, always focusing on preventing acute and chronic neurologic disease produced by virus reactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG032958-06
Application #
8608702
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (02))
Program Officer
Mackiewicz, Miroslaw
Project Start
2009-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
6
Fiscal Year
2014
Total Cost
$1,968,529
Indirect Cost
$525,194
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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