This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the period immediately following infection, many viruses cause a transient, type I interferon-dependent lymphopenia. The reason that mammalian hosts adopt such a strategy has been the subject of considerable speculation, but few proposals have been completely satisfactory. Recently, we made the unexpected discovery that a strain of lymphocytic choriomeningitis virus (LCMV) that is normally rapidly cleared by immmunocompetent mice?the Armstrong strain?induces a profound lymphopenia, but the clone 13 strain, which establishes a high level chronic infection, does not. In order to test the hypothesis that failure of clone 13 to induce lymphopenia was associated with failure of mice to clear clone 13, we induced transient lymphopenia during the acute phase of infection by treatment with drug FTY720, a sphingosine analog that sequesters lymphocytes in lymphoid organs by blocking signals required for exit. The results were stunning: a transient, three day course of FTY720 at days 0, 1, and 2 of infection promoted complete clearance of clone 13, including from organs such as kidneys where virus normally persists for months. We then obtained a result that is potentially even more important: a transient course of FTY720 given at 30 days post clone 13 infection also induced complete clearance of virus. In both experiments, clearance was completely dependent upon CD4 cells, demonstrating that the drug is not acting directly on virus. These discoveries raise a number of important questions that are being studied in this grant: exploration of mechanisms through which FTY720 is promoting clearance of LCMV;determining whether FTY720 also induces reversal of LCMV-induced generalized immunosuppression;asking whether FTY720 also improves immune responses to other viral infections. Treatment with FTY720, which acts on host-immune cells and has no direct specific antiviral effects, might prove useful in treating chronic viral infections in humans, such as HIV, HBV, or HCV.
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