February 2009

Document Type


Degree Name



Dept. of Molecular Microbiology and Immunology


Oregon Health & Science University


Murine cytomegalovirus (MCMV) is a well-studied model of β-herpesvirus infection. It generates a robust CD8 T cell response and asymptomatic infection in immunocompetent mice. The CD8 T cell response is established even though, like all herpesviruses studied, MCMV encodes genes that interfere with antigen presentation via major histocompatibility complex(MHC) class I. In vitro, these genes robustly prevent CD8 T cells from killing infected cells. Therefore, it was expected that a mutant virus lacking the MHC class I immune evasion genes would have impaired viral fitness in vivo. The mutant virus has previously been shown to be impaired in a bone marrow transplant model of MCMV infection. Our laboratory is interested, however, in the immunobiology of MCMV infection of immunocompetent mice. For my thesis work, I set out to identify the impact of these immune evasion genes in vivo by studying the MCMV-specific CD8 T cell response and viral loads following infection with both wild type and mutant virus. I first embarked on a study to further characterize the CD8 T cell response to wild type MCMV infection of mice on a variety of genetic backgrounds. It was not entirely clear what factors contributed to the magnitude and immunodominance hierarchy of the CD8 T cell response, and my findings suggest that genes outside of the MHC complex play a significant role. I then asked how the MHC class I immune evasion genes impact acute and chronic infection of mice with different genetic backgrounds. This work found no new evidence for a role for these genes in vivo, but corroborated the finding that the genes benefit viral growth in the salivary glands of MCMV-susceptible mice. To further probe why the MHC class I immune evasion genes are conserved in MCMV given the relatively subtle phenotype in the salivary glands, I established a model of more natural infection conditions. I expected that the evolutionary benefit of the genes might be more apparent under infection conditions that were more similar to those under which the virus evolved. Mice infected under more natural conditions (low dose and different routes of infection) appear to control the mutant virus better than wild type virus, although immune control of both viruses was variable and no firm conclusions could be drawn. These studies have supported the conclusion that the MHC class I immune evasion genes are conserved in order to benefit viral transmission in immunocompetent mice. My work also called attention to the variability in our model and this has led us to reexamine the benefits of our model and what questions it is best suited to answer.




School of Medicine



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