The Role of Leukocyte Sequestration in the Control of Viral Infections

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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 of the 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 the failure of clone 13 to induce lymphopenia was associated with the failure of mice to clear clone 13, we induced transient lymphopenia during the acute phase of infection by treatment with the drug FTY720, a sphingosine analog that sequesters lymphocytes in lymphoid organs by blocking signals required for their exit. The results were stunning: a transient, three day course of FTY720 at days 0, 1, and 2 of the infection promoted complete clearance of clone 13, including from organs such as the kidneys where the 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 the virus. In both experiments, clearance was completely dependent upon CD4 cells, demonstrating that the drug is not acting directly on the virus. These discoveries raise a number of important questions that we will address in this grant. In Aim 1, we will explore the mechanisms through which FTY720 is promoting clearance of LCMV. In Aim 2, we will ask whether FTY720 also induces reversal of LCMV-induced generalized immunosuppression. Finally, in Aim 3, we will ask whether FTY720 also improves immune responses to other viral infections. For these experiments we will turn to four well established mouse models of viral infection: lethal intranasal infection with vaccinia virus, lethal intranasal infection with influenza virus, infection of newborn tumor-susceptible mice with polyoma virus, and establishment of latent infection with gammaherpesvirus 68. Treatment with FTY720, which acts on hostimmune cells and has no direct specific antiviral effects, might prove useful in treating chronic viral infections in humans, such as HIV, HBV, or HCV.