Project Summary/Abstract Chronic viral infections continue to cause significant morbidity and mortality in humans. Viruses often evade or suppress the host immunity to establish persistent infections. The clone 13 strain (Cl 13) of lymphocytic choriomeningitis virus (LCMV) induces a profound immune suppression and persists in the mouse. LCMV Cl 13 infection of mice has served as a valuable model system for the mechanistic study of viral regulation of host immunity and virus persistence. Sphingosine kinase (SK) 2 mediates the synthesis of sphingosine 1-phosphate (S1P) from sphingosine and controls diverse cellular conditions. However, the function of SK2 in host immune responses to virus infection remains poorly understood. The preliminary data demonstrate that SK2 deficiency in mice results in heightened T cell responses to LCMV Cl 13 infection, leading to lethal immunopathology associated with kidney disease. The data also indicate that LCMV Cl 13 increases the activation of SK2 in CD4+ T cells, which inhibits the expansion of virus-specific T cells. Importantly, the oral administration of the SK2-specific inhibitor into LCMV Cl 13-infected mice accelerates the clearance of the persistent infection. Therefore, the following research aims are developed to uncover the regulatory function of SK2 in virus- induced immune suppression, immune pathology, and virus persistence. First, the role of SK2 in CD4+ T cell suppression will be investigated during persistent LCMV Cl 13 infection as well as using human T cells from patients chronically infected with viruses. Second, the molecular mechanism by which SK2 suppresses virus- specific CD4+ T cell responses and restricts immune pathology will be determined upon LCMV infection. Lastly, the proposed study will further determine the therapeutic efficacy of the SK2-specific inhibitor during persistent LCMV infection and assess the features of the host immunity regulated by SK2 inhibition. Taken together, this research is expected to elucidate the mechanism by which SK2 regulates virus-specific T cell responses, and to define the function of SK2 in the imbalanced immune mechanism that can cause either immune pathologic kidney disease or persistent viral infection. The project could provide a framework for developing new immune therapeutic interventions for controlling chronic virus infections.