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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Languages: English
Types: Doctoral thesis
Subjects: QR180, R1

Classified by OpenAIRE into

mesheuropmc: viruses, biochemical phenomena, metabolism, and nutrition, virus diseases
HCMV is a ubiquitious p herpesvirus that usually causes asymptomatic primary infection. Individuals infected with HCMV mount a strong immune response that suppresses persistent viral replication and is paramount for the prevention of HCMV disease. HCMV encodes a large number of immunomodulatory functions that modulate both the innate and adaptive arms of the immune system. The project undertaken in this thesis was to investigate and characterise immunomodulatory functions encoded by HCMV. A novel and highly efficient method of Natural Killer (NK) cell cloning was developed to investigate modulation of the NK response by HCMV. This technology was utilised to further investigate the finding that CD94/NKG2A+ NK cells are inhibited by UL40-stabilised HLA-E. Analyses of polyclonal NK cell responses and NK clones showed that more CD9410 than CD94hl NK cells were activated by HCMV strain AD169 in comparison to uninfected targets. Flow cytometry showed that there was an increase in the frequency of NK cells expressing the activatory receptor CD94/NKG2C and a decrease in the frequency of cells expressing the inhibitory receptor CD94/NKG2A in HCMV seropositive individuals. The response of NK clones expressing CD94/NKG2A or CD94/NKG2C to targets infected with strain AD169 or RAdUL40 indicated that some CD94/NKG2A clones can be inhibited by gpUL40 while some CD94/NKG2C clones can be activated by gpUL40. Comparative analysis of NK responses to HCMV strain Towne, indicated that strain Towne encoded a novel NK modulatory function that differentially targeted the CD94to and CD94hi NK cell subset in certain individuals. HCMV strain Toledo is known to encode a powerful inhibitor of NK function. Analysis of polyclonal NK cell responses mapped this inhibitory function to gpUL141. In depth analysis of 98 NK clones demonstrated that gpUL141 inhibited a large proportion of NK cells and this was independent of CD94 expression. The initial aim of this study was to characterise the immunomodulatory function of pp65, an HCMV protein that has previously been shown by others to abrogate recognition of HCMV infected cells by HCMV-IE1 specific CTL. Fluorescence microscopy showed that pp65 did not alter the localisation of IE1 and a yeast two-hybrid assay indicated that there was no direct interaction between these 2 proteins. A functional assay using IE1 specific CTL was not performed because sufficient numbers of peptide specific CTL could not be cultured. Nevertheless, this study has contributed to the characterisation of powerful HCMV immunomodulatory functions that selectively target NK cell subsets and are sufficient to alter frequencies of cells in the innate immune system. The results presented here enhance our understanding of HCMV pathogenesis, the regulation of NK cell function and the biology of the innate immune system.
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