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
Birlea, Marius; Nagel, Maria A; Khmeleva, Nelly et al. (2014) Varicella-zoster virus trigeminal ganglioneuritis without rash. Neurology 82:90-2
Nagel, Maria A; Gilden, Don (2014) Neurological complications of varicella zoster virus reactivation. Curr Opin Neurol 27:356-60
Nagel, Maria A; Khmeleva, Nelly; Choe, Alexander et al. (2014) Varicella zoster virus (VZV) in cerebral arteries of subjects at high risk for VZV reactivation. J Neurol Sci 339:32-4
James, Stephanie F; Traina-Dorge, Vicki; Deharo, Eileen et al. (2014) T cells increase before zoster and PD-1 expression increases at the time of zoster in immunosuppressed nonhuman primates latently infected with simian varicella virus. J Neurovirol 20:309-13
Teodoro, Tiago; Nagel, Maria A; Geraldes, Ruth et al. (2014) Biopsy-negative, varicella zoster virus (VZV)-positive giant cell arteritis, zoster, VZV encephalitis and ischemic optic neuropathy, all in one. J Neurol Sci 343:195-7
Birlea, Marius; Cohrs, Randall J; Bos, Nathan et al. (2014) Search for varicella zoster virus DNA in saliva of healthy individuals aged 20-59 years. J Med Virol 86:360-2
Liberman, Ava L; Nagel, Maria A; Hurley, Michael C et al. (2014) Rapid development of 9 cerebral aneurysms in varicella-zoster virus vasculopathy. Neurology 82:2139-41
Nagel, Maria A; Gilden, Don (2014) Update on varicella zoster virus vasculopathy. Curr Infect Dis Rep 16:407
Nagel, Maria; Gilden, Don (2014) Editorial commentary: varicella zoster virus infection: generally benign in kids, bad in grown-ups. Clin Infect Dis 58:1504-6
Baird, Nicholas L; Bowlin, Jacqueline L; Yu, Xiaoli et al. (2014) Varicella zoster virus DNA does not accumulate in infected human neurons. Virology 458-459:1-3

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