Cytomegalovirus is a beta-herpesvirus that establishes chronic/persistent infections in the majority of people world-wide. Despite the fact that the virus persists at extremely low levels, the immune system, and T cells in particular, become obsessed with the infection: CMV-specific CD8 T cells can regularly comprise 10% of all CD8 T cells in the peripheral blood of infected individuals. Data from mice infected with murine cytomegalovirus (MCMV) have shown that CDS T cells begin accumulating after acute infection until reaching the high numbers seen in circulation during chronic infection, a process known as memory inflation. In both humans and mice, these inflated T cells bear a phenotype that is indicative of extensive antigen-driven differentiation. Yet the T cells remain functional and retain proliferative potential even at late times post infection. We have recently shown that during chronic infection, these MCMV-specific T cell populations divide only sporadically, are short-lived in circulation and are being constantly replaced as they disappear. Thus, these circulating CMV-specific T cells, that exist in large enough numbers to perturb the total CD8 T cell pool, are highly dynamic. We postulate that this constant decay and replacement of differentiated cells avoids the T cell dysfunction that is seen in other models of chronic infection. Ultimately however, CMV infection is associated with large T cell clonal expansions in aged individuals, suggesting that eventually, the dynamic equilibrium that was established early in chronic infection is lost. These clonal expansions consist of dysfunctional T cells and their presence is associated with an immune risk phenotype in old age. We hypothesize that these expansions arise because some cells divide rather than decay as infected individuals get older. It is important to understand how the dynamic equilibrium is established and maintained in healthy adults in order to understand how it is lost with age. The experiments outlined in this grant are designed to locate and follow the cells that respond to viral antigen and produce differentiated, short-lived progeny during chronic infection and to dissect the impact of viral gene expression on the accumulation of CD8 T cells.
