Plasmacytoid Dendritic Cells (PDC) produce copious amounts of IFN-a in response to TLR-7 or -9 stimulation and serve as a link between the innate and adaptive immune systems. In HIV infection, there is a gradual depletion of PDC as well as a functional deficiency in remaining circulating PDC. The mechanism of PDC depletion is not yet understood. We have demonstrated using imaging flow cytometry (ImageStream®) that PDC preferentially take up membrane and cytoplasm from HSV and Influenza infected cells in an endocytic process called "nibbling" that results in IFN-α production by the PDC. Using acutely HIVIIIB infected CD4 T cells or chronically HIVIIIB infected H9 T cells, PDC preferentially form conjugates with HIVIIIB infected vs uninfected T cells, but, rather than being nibbled, the majority of these encounters lead to PDC/infected T cell fusions. Acutely infected CD4 T cells but not chronically-infected H9 cells stimulated PDC to produce IFN-α, albeit it lower levels than other TLR7/9 inducers. Fusions were blocked with the addition of the specific fusion inhibitors (T-20 or AMD-3100), but there was no increase in conjugate formation or uptake of material. We hypothesize that this successful subversion of PDC nibbling and IFN-α production by HIV-infected cells contributes to loss of PDC and the deficient IFN-α production seen in HIV-infected patients. Supported by AI26806.