Cytomegaloviruses (CMVs) are species specific beta herpesviruses that establish life long infection in the majority of mammals. This lifelong residence is provokes very large CD8 and CD4 T cell responses in the majority of hosts, that have a characteristic """"""""effector memory"""""""" (TEM) phenotype and tend to increase in numbers with age, sometimes dominating the entire CDST cell compartment in the elderly. Two paradoxes underlie this signature response. First, the majority of CDST cells have a poor ability to recognize infected cells, due to the function of CMVs genes that interfere with antigen presentation. How are these T cells primed? Second, although latent virus is present in infected hosts, there is little evidence of virus activity. Where does the antigen come from that drives the response? These questions will be addressed using the C57BL/6 mouse model of CMV infection. The first specific aim of this proposal is to test the hypothesis that cross-presentation is responsible for priming that majority of the CDST cell response. To address this aim, a unique set of tools is being assembled: the immunodominance hierarchy amongst 25 CMV epitopes recognized by CDS T cells from C57BL/6 mice will be measured. Mutant viruses lacking both the ability to impair antigen presentation and the ability to impair the expression of co-stimulatory molecules on dendritic cells are being generated, and a mouse model of impaired cross presentation will be used. There is a marked alteration in the main antigens recognized between acute and chronic infection.
The second aim addresses the cause of that shift. The ability of the immune system to impact viral activity in different cell types, particularly endothelial cells, will be addressed as a primary cause of this altered immunodominant. Finally, the paradox that the large, inflating T cell response is maintained by viral activity that is below the threshold of detection will be addressed. The TEM phenotype of the CDST cells will be evaluated. Are these cells equivalent to the transitory TEM population observed following resolution of acute infection, resulting from constant restimulation with antigen? Or do they represent a quiescent, long-lived population, as has been proposed for human TEM of a similar phenotype?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047206-08
Application #
7738501
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Beisel, Christopher E
Project Start
2000-04-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
8
Fiscal Year
2010
Total Cost
$373,909
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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
Freeman, Bailey E; Raué, Hans-Peter; Hill, Ann B et al. (2015) Cytokine-Mediated Activation of NK Cells during Viral Infection. J Virol 89:7922-31
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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