Document Type


Degree Name



Dept. of Molecular Microbiology and Immunology


Oregon Health & Science University


Development of attenuated viruses is important to the therapeutic vaccine strategy against viral infections, as the goal of a live-strain vaccine is to provide the most robust immune response in the least pathogenic package. In this thesis the goal is not to develop a new CMV based vaccine, but to understand the mechanism that drives a CD8 T cells response in a replication-deficient murine cytomegalovirus (MCMV) infection. Murine cytomegalovirus infection, like Human CMV, produces a robust chronic immune response, with the pool of Ag-specific CD8 T cells to CMV as high as 10% in the blood. What is less known is the acute CD8 T cell response to HCMV, as primary infection is often benign and unidentified in immune-competent individuals. Using the MCMV model we are able to identify the acute CD8 T cell response and track changes of these responses into the chronic stage of infection. The role of viral replication is important to the development of the antiviral CD8 T cell response as it produces viral antigen and initiates an inflammatory response (which provides co-stimulation) that is essential for the priming of naïve CD8 T cells. Therefore, blocking viral replication will reduce both available antigen and inflammation. My initial hypothesis of the CD8 T cell response to a replication-deficient MCMV was that the response would be weaker in comparison to a replication-competent infection. Surprisingly, the acute CD8 T cell response in a replication-deficient MCMV infection was increased and these antigen-specific CD8 T cells formed a greater memory population. The goal of this thesis is to characterize this CD8 T cell response and find a mechanism that helps explain this elevated response. In order to investigate the role of viral replication in the CD8 T cell response to MCMV infection, we infected mice with a recombinant MCMV (MCMV-TK), where viral replication can be inhibited when mice are treated with antiviral drug Famcyclovir. MCMV-TK can replicate to measurable levels of titers, comparable to wild-type MCMV. However, Famcyclovir renders MCMV-TK replication-deficient as it acts as a DNA chain terminator during viral genome synthesis, thus producing undetectable titers at 3 days post-infection. Infection of Famcyclovir treated C57BL/6 mice with a MCMV-TK resulted in priming of CD8 T cells and an enhanced T cell response at day 7 post-infection. This was a 2–3 fold enhancement of the CD8 T cell response in comparison to a replication-competent infection. Investigation of the dendritic cell (DC) numbers during acute infection show that conventional DC (cDC) numbers decline in a replicating infection, while cDC numbers are preserved in a replication-deficient infection. Re-introducing inflammation, specifically type I IFNs, into mice with a replication-deficient infection lowers CD8 T cell responses to wild-type levels and decreases DC numbers. This work demonstrates a mechanism in which the type I IFN inflammatory response during acute MCMV infection causes a decrease in cDC numbers, and this decrease in cDCs results in less proliferation of CD8 T cells that are dependent on cross-presented antigen.




School of Medicine



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