Varicella zoster virus (VZV) is an ubiquitous human pathogen. Primary infection causes childhood chickenpox, leading to latency in cranial nerve, dorsal root and autonomic ganglia. VZV reactivation, frequent in the elderly and immunocompromised population, results in significant neurological disease. Zoster and postherpetic neuralgia predominate, but many humans develop myelitis, segmental motor weakness, cranial nerve palsies, and a severe, often fatal vasculopathy in the brain. We have also shown that VZV reactivation can produce chronic intense pain in the absence of rash. Although the mechanism controlling VZV latency is not understood, it is likely to depend upon virus gene transcription, thus providing the rationale for our hypothesis that VZV gene expression in human ganglia during latency functions to maintain latent infection. Identification of the VZV genes expressed during latency is critical to understanding latent infection. Until the advent of high throughput array-based technology, such analyses were not feasible, and <20% of the VZV genome has been analyzed for latent virus transcripts. Further, merely identifying the latently transcribed VZV genes is insufficient. Since control of VZV latency is likely to involve virus proteins, characterization of latently expressed viral proteins is also critical to understanding virus gene regulation. Thus, our long-term goal is the detailed characterization, including functional analysis, of VZV genes expressed in latently infected human ganglia.
Our specific aims will: (1) identify latently transcribed VZV genes by transcriptional array analysis, confirm the authenticity of the transcripts by sequencing, and determine the abundance of the virus transcripts by fluorescence-based quantitative (real-time) RT-PCR; (2) construct high affinity epitope-tagged recombinant antibodies to colocalize latently expressed VZV proteins by in situ immunohistochemistry in sections of human ganglia; and (3) initiate protein function analysis using 2-hybrid systems to identify and map protein-protein interactions. We will begin with VZV IE63, the most prevalent and abundant virus transcript detected to date during latency. An in-depth understanding of VZV gene expression and function in latently infected human ganglia will lead to testable models of latent virus gene regulation (in the developing simian varicella virus model) and to therapies designed to reduce morbidity and mortality associated with reactivation of this highly neurotropic human pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS032623-20
Application #
7561082
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
20
Fiscal Year
2008
Total Cost
$384,329
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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:
Ouwendijk, Werner J D; van Veen, Suzanne; Mahalingam, Ravi et al. (2017) Simian varicella virus inhibits the interferon gamma signalling pathway. J Gen Virol :
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
Birlea, Marius; Owens, Gregory P; Eshleman, Emily M et al. (2013) Human anti-varicella-zoster virus (VZV) recombinant monoclonal antibody produced after Zostavax immunization recognizes the gH/gL complex and neutralizes VZV infection. J Virol 87:415-21
Mueller, Niklaus H; Bos, Nathan L; Seitz, Scott et al. (2012) Recombinant monoclonal antibody recognizes a unique epitope on varicella-zoster virus immediate-early 63 protein. J Virol 86:6345-9
Nagel, Maria A; Bert, Robert J; Gilden, Don (2012) Raeder syndrome produced by extension of chronic inflammation to the internal carotid artery. Neurology 79:1296-7
Wolf, James; Nagel, Maria A; Mahalingam, Ravi et al. (2012) Chronic active varicella zoster virus infection. Neurology 79:828-9
Brennan, Kathryn M; Galban-Horcajo, Francesc; Rinaldi, Simon et al. (2011) Lipid arrays identify myelin-derived lipids and lipid complexes as prominent targets for oligoclonal band antibodies in multiple sclerosis. J Neuroimmunol 238:87-95
Haug, Aaron; Mahalingam, Ravi; Cohrs, Randall J et al. (2010) Recurrent polymorphonuclear pleocytosis with increased red blood cells caused by varicella zoster virus infection of the central nervous system: Case report and review of the literature. J Neurol Sci 292:85-8
Mahalingam, Ravi; Traina-Dorge, Vicki; Wellish, Mary et al. (2010) Latent simian varicella virus reactivates in monkeys treated with tacrolimus with or without exposure to irradiation. J Neurovirol 16:342-54

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