Depletion of dendritic cells enhances susceptibility to cell-free infection of HTLV-1 in CD11c-DTR transgenic mice (45.11)

Abstract

Abstract Human T-cell leukemia virus type 1 (HTLV-1) is associated with HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T-cell leukemia. The genesis of these diseases is believed to be associated with the route and mode (cell-free versus cell-associated) of primary infection. To explore the role of DCs during early HTLV-1 infection in vivo, we used a chimeric HTLV-1 with a replaced envelope gene from Mo-MLV to allow HTLV-1 to fuse with murine cells, which are generally not susceptible to infection with human retroviruses. We also used a CD11c-DTR transgenic mouse that permits conditional transient depletion of CD11c+ DCs. We infected these mice with HTLV-1 using both cell-free and cell-associated infection routes in the absence and presence of DCs. The ablation of DCs led to an enhanced susceptibility to infection with cell-free, but not cell-associated HTLV-1 in both the CD4 and non-CD4 fractions, as measured by the proviral load. Infection with cell-free virus in the absence of DCs was also found to have increased levels of Tax mRNA. Moreover, depletion of DCs significantly dampened the cellular immune response against both cell-free and cell-associated virus. These results uniquely differentiate the involvement of DCs in early cell-free versus late cell-associated infection of HTLV-1 and highlight a significant aspect of viral immunopathogenesis related to the progression of ATL and HAM/TSP after the initial infection.