IMMUNE CONTROL AND EVASION IN MURINE CMV INFECTION

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DESCRIPTION (provided by applicant): Cytomegaloviruses (CMVs) encode multiple genes that function to impair MHC class 1-restricted antigen 1 presentation to cytotoxic T lymphocytes (CTL). It has been assumed that these genes are necessary to enable CMV to persist in the host in the presence of a primed immune response, but this has not been demonstrated. This application uses the murine cytomegalovirus model of infection of its natural host (the mouse) to ask what effect the immune evasion genes have on the course of MCMV infection, and how they achieve this effect. A panel of mutant viruses lacking each of the immune evasion genes of MCMV- m4, m6 and m152-alone and in combination, has been generated using bacterial artificial chromosomes technology. These will be used to analyze the effect of the immune evasion genes on the CTL response, and the consequent effect on virus persistence and replication. In order to be able to study the CTL response, the immunodominant MCMV antigens recognized by H-2b mice will first be identified. An expression library containing the entire MCMV genome expressed in short DNA fragments has been generated and will be screened using MCMV-specific CTL clones to identify the antigens they recognize. MCMV infects macrophages and dendritic cells as well as epithelial and other somatic cells in vivo. Antigen presentation by professional antigen presenting cells is likely to be the major determinant of the size of the CTL response, and it has been reported that the immune evasion genes do not function effectively in macrophages. However, data suggesting that the immune evasion genes may function in some macrophages is presented here. A comprehensive analysis of the function of the immune evasion genes on antigen presentation by Kb and Db in primary macrophages and dendritic cells will be carried out and contrasted with the effect seen in mouse embryo fibroblasts. This information will be used to interpret experiments measuring the CTL response and virus load in mice infected with wildtype virus and viruses lacking immune evasion genes.