Varicella-zoster virus (VZV) causes varicella and herpes zoster. Our goal is to improve knowledge about how this common pathogen causes disease and about protection provided by natural and vaccine-induced immunity. Glycoproteins are likely to be host range determinants for T cells and skin, which are critical target cells during VZV infection. Our focus is on glycoproteins, gI (ORF67) and gE (ORF68). The effect of gI or gE mutations made in cosmids, on VZV replication will be determined in vitro. Infectivity for human CD4+ and CD8+ T cells or skin will be assessed in vivo in the SCIDhu mouse model of VZV pathogenesis, which reveals critical roles for VZV proteins that are completely dispensable in tissue culture. T cell tropism will also be investigated in thymic organ cultures and II23 cells, a CD4+ T cell hybridoma, using green fluorescent protein (gfp)-labeled VZV. VZV gI and gE effects on epithelial cells will be evaluated in MDCK cells. The vaccine strain, V-Oka, will be compared with its parent, P-Oka, to determine whether gE or gI mutations explain V-Oka attenuation. VZV infects T cells in the naive host and spreads before VZV specific immunity is induced. We have found that VZV interferes with cell surface expression of major histocompatibility (MHC) class I and class II. Our goals are to identify viral immunomodulatory proteins that allow VZV to escape from immune surveillance and to determine whether skin homing receptors facilitate transport of infected T cells to skin. Whether these mechanisms function at skin sites during natural infection will be determined in biopsies from acute varicella lesions. Rapid acquisition of VZV specific T cell responses correlates with mild varicella and maintenance of latency. We propose to address important questions about adaptive VZV immunity with new methods to measure CD4+ and CD8+ T cell responder frequencies against dominant viral proteins, gE and the immediate early tegument/transactivating protein, IE62. We will examine differences in protection afforded by natural and vaccine-induced immunity, diminished immunogenicity of varicella vaccine in adults, and declining VZV T cell responses with aging. Quantitative comparisons of CD4+ and CD8+ recognition of gE and IE62 protein and peptides will be made using intracellular cytokine assays. Peptides appropriate for synthesis as MHC class I and class II tetramers will be identified and used to enumerate VZV specific responder T cells in CD4+ and CD8+ subsets. These parallel investigations of VZV pathogenesis and immunity are directly linked by their practical relevance for improving live attenuated varicella vaccines.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Beisel, Christopher E
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Stanford University
Schools of Medicine
United States
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Zerboni, Leigh; Sung, Phillip; Sommer, Marvin et al. (2018) The C-terminus of varicella-zoster virus glycoprotein M contains trafficking motifs that mediate skin virulence in the SCID-human model of VZV pathogenesis. Virology 523:110-120
Zerboni, Leigh; Sung, Phillip; Lee, Gordon et al. (2018) Age-Associated Differences in Infection of Human Skin in the SCID Mouse Model of Varicella-Zoster Virus Pathogenesis. J Virol 92:
Sen, Nandini; Sung, Phillip; Panda, Arjun et al. (2018) Distinctive Roles for Type I and Type II Interferons and Interferon Regulatory Factors in the Host Cell Defense against Varicella-Zoster Virus. J Virol 92:
Sullivan, Nicole L; Reuter-Monslow, Morgan A; Sei, Janet et al. (2018) Breadth and Functionality of Varicella-Zoster Virus Glycoprotein-Specific Antibodies Identified after Zostavax Vaccination in Humans. J Virol 92:
Oliver, Stefan L; Yang, Edward; Arvin, Ann M (2017) Dysregulated Glycoprotein B-Mediated Cell-Cell Fusion Disrupts Varicella-Zoster Virus and Host Gene Transcription during Infection. J Virol 91:
François, Sylvie; Sen, Nandini; Mitton, Bryan et al. (2016) Varicella-Zoster Virus Activates CREB, and Inhibition of the pCREB-p300/CBP Interaction Inhibits Viral Replication In Vitro and Skin Pathogenesis In Vivo. J Virol 90:8686-97
Khalil, Mohamed I; Che, Xibing; Sung, Phillip et al. (2016) Mutational analysis of varicella-zoster virus (VZV) immediate early protein (IE62) subdomains and their importance in viral replication. Virology 492:82-91
Oliver, Stefan L; Yang, Edward; Arvin, Ann M (2016) Varicella-Zoster Virus Glycoproteins: Entry, Replication, and Pathogenesis. Curr Clin Microbiol Rep 3:204-215
Sen, Nandini; Arvin, Ann M (2016) Dissecting the Molecular Mechanisms of the Tropism of Varicella-Zoster Virus for Human T Cells. J Virol 90:3284-7
Sen, Nandini; Mukherjee, Gourab; Arvin, Ann M (2015) Single cell mass cytometry reveals remodeling of human T cell phenotypes by varicella zoster virus. Methods 90:85-94

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