Transient FTY720 treatment promotes immune-mediated clearance of a chronic viral infection

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  • This article was retracted on 08 April 2010

Abstract

For a wide variety of microbial pathogens, the outcome of the infection is indeterminate. In some individuals the microbe is cleared, but in others it establishes a chronic infection, and the factors that tip this balance are often unknown. In a widely used model of chronic viral infection, C57BL/6 mice clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), but the clone 13 strain persists1,2. Here we show that the Armstrong strain induces a profound lymphopenia at days 1–3 after infection, but the clone 13 strain does not. If we transiently augment lymphopenia by treating the clone-13-infected mice with the drug FTY720 at days 0–2 after infection, the mice successfully clear the infection by day 30. Clearance does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Notably, FTY720 treatment of an already established persistent infection also leads to viral clearance. In both models, FTY720 treatment preserves or augments LCMV-specific CD4 and CD8 T-cell responses, a result that is counter-intuitive because FTY720 is generally regarded as a new immunosuppressive agent3. Because FTY720 targets host pathways that are completely evolutionarily conserved, our results may be translatable into new immunotherapies for the treatment of chronic microbial infections in humans.

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Figure 1: LCMV Armstrong but not clone 13 induces profound lymphopenia at days 2 and 3 after infection.
Figure 2: Low-dose short-term FTY720 treatment of clone-13-infected mice prevents the establishment of a persistent LCMV infection.
Figure 3: Low-dose short-term FTY720 treatment clears an established persistent clone 13 infection.

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Acknowledgements

We would like to thank R. Ahmed for his support and guidance during the project; D. Liotta for the use of his mass spectrometer; and the members of the Ahmed and the Altman laboratories for discussions. This work was supported by National Institute of Health grant numbers AI042373 (to J.D.A.) and 5F32AI062002 (M.P.-L.).

Author Contributions M.P.-L. originated and designed the project, analysed the results and co-wrote the manuscript with J.D.A. who also provided guidance and support throughout the project. N.B.M. performed viral load assays. S.T.P. measured S1P levels. P.A.R. was involved in preliminary experiments.

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Correspondence to Mary Premenko-Lanier or John D. Altman.

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Premenko-Lanier, M., Moseley, N., Pruett, S. et al. Transient FTY720 treatment promotes immune-mediated clearance of a chronic viral infection. Nature 454, 894–898 (2008) doi:10.1038/nature07199

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