COXSACKIE MYOCARDITIS AND VIRAL PERSISTENCE IN THE HEART

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Coxsackieviruses, members of the picornavirus family, are important human pathogens. Coxsackievirus B3 (CVB3), is a common associated factor in human subacute, acute, and chronic myocarditis. In young adults CVB3 infections may cause cardiac arrhythmias and acute heart failure; and chronic disease may supervene, leading to dilated cardiomyopathy, requiring transplantation, or to death. To better understand the pathogenesis of this disease, several mouse model systems have been established, which appear to parallel many aspects of the human disease process. We have begun to investigate the mechanisms underlying CVB myocarditis. The goals of this proposal are: 1. To further investigate the immune determinants of CVB3 myocarditis. What viral proteins do CD4+ and CD8+ T cells recognize, and how do these cells interact? Is the Fas pathway involved in disease? 2. To investigate the roles of antibodies and T cells in control of CVB3 infection and disease. Which virus proteins can protect against CVB? Is priming of CD8+ T-cell immunity beneficial or harmful? 3. To determine the cells infected during acute and persistent CVB3 infection. Does CVB interact with B cells early in infection? What other cells are infected? What cells are infected during virus persistence? 4. To begin evaluation of the nature of persistent CVB3. We have developed a system in which persistently-infected mice contain high levels of infectious virus. Does this persisting virus differ from the original? 5. To evaluate treatments for persistent CVB3 infection. Antibody- deficient humans often suffer from chronic picornavirus infections, which are frequently refractory to treatment. Our mouse model of persistence in the absence of B cells will be used for testing different treatment regimens.