Zoster (shingles) is a common disorder of the elderly characterized by severe dermatomal pain and rash. Zoster and its attendant neurologic complications of postherpetic neuralgia (PHN), encephalitis and granulomatous arteritis, result from reactivation of varicella zoster virus (VZV), a ubiquitous human herpesvirus that becomes latent in ganglia after childhood chickenpox. Our continuing analysis of human ganglia and mononuclear cells has revealed important differences between VZV, herpes simplex and Epstein-Barr virus, both in the tissue targeted for latenCy and the extent of viral gene expression, supporting our hypothesis that the mechanism by which each herpesvirus is reactivated is unique. Therefore, information on the cell type(s) infected, the configuration of VZV DNA, and the extent of VZV gene expression in latently infected ganglia is crucial to the eventual control of virus reactivation. Using our bank of well-characterized human ganglia, our cloned and mapped VZV DNA fragments, and the complete sequence of the VZV genome, we have shown in the past 5 years that latent VZV is present in many ganglia at all levels of the human neuraxis, that more than one region of the virus genome is present, that there are approximately 6-31 copies of VZV DNA/105 ganglionic cells, and that VZV gene 21 is transcribed. Furthermore, in anticipation of analyzing the configuration of varicella DNA in latently infected ganglia, we showed by PCR that whereas varicella DNA is linear in virions, it is present as circles or concatemers in infected cells. In the next 5 years, we will exploit our expertise in PCR combined with in situ hybridization to define the exclusive cell type(s) harboring latent VZV, and will continue to analyze the configuration of VZV DNA during latency, including its possible integration into cell DNA. From our well-characterized cDNA library prepared from latently infected human ganglia, we will determine the full length of latent VZV gene 21 RNA, the known sequence of which will then be used to produce gene 21-specific peptides and antibody for analysis of ganglia. We will continue our search for and analysis of any additional VZV-specific transcripts that may be present in our ganglionic cDNA library. These studies will yield information on the molecular basis of viral latency and reactivation, which provides the foundation for future studies designed to eradicate neurologic disease in the elderly caused by VZV.
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