Cytomegalovirus (CMV) infection is characterized by enormous effector/memory T cell responses that are maintained at high levels for life- a phenomenon known as memory inflation. We have reported that """"""""inflationary memory"""""""" cells are in fact short lived effector cells continuously differentiating from true memory cells generated early during infection. The true memory cells are not readily transferred from the spleen of an infected host to an infected recipient, and we suggest that they reside in a stromal niche. We have also shown that a single cycle CMV which is unable to spread beyond the cells it infects upon first entering the body drives surprisingly robust memory inflation. These two findings define the paradox that we seek to unravel in this project: how can a tiny number of infected cells present antigen to keep the immune system constantly activated without being subject to immune eradication? We first ask whether the information about viral presence is transmitted to T cells through direct or cross presentation of viral antigen. This will be accomplished by generating a virus expressing Kb in order to limit antigen presentation to directly infected cells. We will next use an iterative process of organ digestion, cell sorting and bioassays to identify the cells that carry the viral genome and the cells that present antigen to T cells. As an alternative approach, we will generate virus which can be used to infect cre mice to limit antigen expression to particular tissues or cell types. Finally, we will characterize the latently infected cells with respect to their immunological phenotype, their viral gene expression, and their sufficiency for driving memory inflation upon co-adoptive transfer with memory CD8 and CD4 T cells. Understanding the viral program that drives memory inflation will enable us to intelligently engineer CMV-vectors as vaccines to generate potent immune responses. It will also help us to understand CMV's role in certain chronic diseases, and its putative association with immunosenescence.

Public Health Relevance

Cytomegalovirus is a ubiquitous human virus that excites an extremely large immune response from the infected host. This enormous immune response can be harmful, contributing to immunosenescence in the elderly, or helpful, when CMV is used as a vaccine vector. It is not known why the immune response is so large, and the mystery was heightened by our discovery that even a non-infectious CMV vaccine drives an enormous response. The goal of this project is to understand exactly how CMV excites this unprecedented response. Using the non-infectious vaccine, we will find the cells that drive the response and determine how they interact with the immune system to drive the response. This knowledge will be exploited directly in our other work to develop a CMV-based cancer vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense (IHD)
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Beisel, Christopher E
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Oregon Health and Science University
Schools of Medicine
United States
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Loo, Christopher P; Snyder, Christopher M; Hill, Ann B (2017) Blocking Virus Replication during Acute Murine Cytomegalovirus Infection Paradoxically Prolongs Antigen Presentation and Increases the CD8+ T Cell Response by Preventing Type I IFN-Dependent Depletion of Dendritic Cells. J Immunol 198:383-393
Murray, Susan E; Nesterenko, Pavlo A; Vanarsdall, Adam L et al. (2017) Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans. J Exp Med 214:1889-1899
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Farrington, Lila A; Smith, Tameka A; Grey, Finn et al. (2013) Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection. J Immunol 190:3410-6
Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L et al. (2011) Sustained CD8+ T cell memory inflation after infection with a single-cycle cytomegalovirus. PLoS Pathog 7:e1002295
Schlub, Timothy E; Sun, Joseph C; Walton, Senta M et al. (2011) Comparing the kinetics of NK cells, CD4, and CD8 T cells in murine cytomegalovirus infection. J Immunol 187:1385-92
Snyder, Christopher M; Allan, Jane E; Bonnett, Elizabeth L et al. (2010) Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells. PLoS One 5:e9681
Snyder, Christopher M; Loewendorf, Andrea; Bonnett, Elizabeth L et al. (2009) CD4+ T cell help has an epitope-dependent impact on CD8+ T cell memory inflation during murine cytomegalovirus infection. J Immunol 183:3932-41
Doom, Carmen M; Turula, Holly M; Hill, Ann B (2009) Investigation of the impact of the common animal facility contaminant murine norovirus on experimental murine cytomegalovirus infection. Virology 392:153-61
Snyder, Christopher M; Cho, Kathy S; Bonnett, Elizabeth L et al. (2008) Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29:650-9

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