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The role of plasmacytoid dendritic cells (pDC) and interferon alpha (IFNα) in HIV-1 infection is still unclear. On one hand, HIV-1 disease is associated with a progressive decline of pDC, which displays reduced ability to produce IFNα after in vitro challenge. On the other hand, high IFNα serum levels in HIV-1-infected individuals have been proposed to promote immune hyper-activation and disease progression.We sought to determine whether disappearance of pDC in HIV-1 disease is due to homing in lymphoid tissues. We also studied IFNα and myxovirus resistance protein A (MxA) expression in unstimulated pDC and correlated these results with selected clinical and laboratory parameters.We found that pDC decline markedly in peripheral blood of patients progressing to disease but at the same time express much higher levels of IFNα and MxA compared to control individuals. On the other hand, we observed steady pDC counts in lymph nodes of HIV-1 patients. The frequency of circulating pDC correlated directly with CD4 cell counts and inversely with viral load. However, we found no correlation between IFNα and MxA expression levels, CD4 counts, and viral load.Circulating pDC decline sharply in the course of HIV-1 disease, but express high levels of IFNα, which may represent a hallmark of systemic immune dysfunction.