Regulation of CD8 T cell responses to polyoma virus infection

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DESCRIPTION (provided by applicant): Persistent viral infections are a major cause of morbidity and mortality. Examples include HIV (resulting in AIDS), Cytomegalqvirus (CMV),. Epstein Barr virus (EBV) (responsible for mononucleosis, and; B cell lymphoma), Hepatitis C (leading to liver destruction), and Human Papiloma Virus (which may result in cervical cancer). Continual surveillance of CDS T cells is required to eliminate or, at minimum, control the spread of these viruses throughout the body. Understanding why CDS T cells are incapable of eliminating a persistent viral pathogen is a critical concern for human health. This proposal attempts to address key factors that may prove to be critical interventions to tilt the balance in favor of the host, allowing the elimination of the virus and the generation of a stable memory CDS T cell pool capable of preventing reinfection. The model for these studies is polyoma virus (PyV), a small, oncogenic DMA virus that infects mice (the natural host). CDS T cell immunity is critical to control tumor formation and outgrowth following infection, and a persistent viral infection can be detected in almost all tissues for life. The first aim of the proposal compares the evolution of PyV-specific T cells primed during acute and persistent phases of infection. These studies are performed using a novel recombinant PyV expressing OVA257-264 within the middle T antigen. Key differences may exist in the restrictions or conditions necessary for optimal priming at different time points, and this novel virus will allow us to clearly address this question using adoptive transfer of OT-I transgenic T cells at various time points post infection. Aim 2 addresses the role of dendritic cells in the priming of CDS T cells in persistent phase infection. Aim 3 involves the manipulation of costimulatory molecules (specifically CD27/CD70). This costimulatory molecule plays a critical role in the maintenance and development of memory CDS T cells. This subaim will also be investigated with adoptive transfer of OT- I transgenic T cells followed by treatment with soluble CD70 during persistent infection. Collectively, these studies should provide critical insights into possible therapeutic interventions to stimulate defective CDS T cell immunity observed in numerous persistent viral infections.