Understanding differences bptween acute and chronic infections is important for the development of therapies to treat and cure chronic diseases. We found that dramatic sequestration of lymphocytes into secondary lympohoid tissues occurs early following acute LCMV Armstrong infection, though not following infection with chronic LCMV clone-13, We hypothesized that the lack of early sequestration during chronic LCMV contributes to the establishment of the infectioa Transient administration of the sequestration drug FTY720 at the time of infection, enhanced immunity and prevented the establishment of chronic LCMV. Additionally, we found that FTY720 treatment cleared a previously established done-13 infection. FTY720 has no antiviral properties therefore its treatment led to immune mediated clearance that is dependent on CD4 T cells, dendetric cells and macrophages. This grants goal is to further understand the immune enhancing effects of FTY720 and apply the findings towards developing therapies for chronic diseases. We hypothesize that transient treatment with FTY720 directly alters the location and interaction of lymphocytes with APCs ?at leads to enhanced immune activation, while indirectly preventing the establishment of chronic infection. This grant will study the mechanism of FTY720s reversion of a dysfunctional immune response. The three aims are: 1) to understand and explore the role of CD4-I- T cells in the enhancement of CD8-I- T cell function during FTY720 treatment. 2) To understand the effects of FTY720 on dendritic cells and macrophages during FTY720 treatment, and on the general maintenance of immune architecture. 3) To measure the coordination of the immune response by determining the kinetics of innate immune activation and how treatment with FTY720 accelerates the activation of the acquired immune response that is key to controlling the infection.
This grant will help to understand the immune enhancing mechanism of the sequestration drug FTY720 when administered transiently during chronic viral infection. This work will be key in designing strategies for using FTY720 to treat human chronic infections such as HIV, hepatitis C and hepatitis B.
| Stamm, Andrew; Valentine, Laura; Potts, Rashaun et al. (2012) An intermediate dose of LCMV clone 13 causes prolonged morbidity that is maintained by CD4+ T cells. Virology 425:122-32 |
| Valentine, Laura; Potts, Rashaun; Premenko-Lanier, Mary (2012) CD8+ T cell-derived IFN-? prevents infection by a second heterologous virus. J Immunol 189:5841-8 |
