title: Transient FTY720 treatment promotes immune-mediated clearance of a chronic viral infection.
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 persists. 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 agent. 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.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Yerkes National Primate Research Center and Emory University School of Medicine, 954 Gatewood Road, Atlanta, Georgia 30329, USA. mflanie@emory.edu
authors.forename: Mary
authors.initials: M
authors.lastname: Premenko-Lanier
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Moseley
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Pruett
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Romagnoli
authors.forename: John D
authors.initials: JD
authors.lastname: Altman
mesh_terms: D000818:Animals; D002908:Chronic Disease; D000068876:Fingolimod Hydrochloride; D008216:Lymphocytic Choriomeningitis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000502:physiology; D008231:Lymphopenia / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine