Abstract
Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur.
Highlights
Plasmacytoid dendritic cells are one of the two main subtypes of human dendritic cells. pDC, like the classical myeloid dendritic cells, are able to present antigens to T cells [1], but have a distinctive feature of producing type I interferons (IFN) [2]. pDC are able to secrete IFN-a at levels up to 1000 fold higher than any other blood cell following viral infection [2]
Each dot represents one individual and bars represent mean. (C) The infected cohorts were stratified according to CD4 T cell counts (.350 and,350 cells/ml) and pDC levels compared as percentages and absolute numbers
A similar decrease in pDC levels was found in untreated HIV-2 and HIV-1 infections in spite of the much lower viremia and slower rate of disease progression that distinguishes HIV-2 disease
Summary
Plasmacytoid dendritic cells (pDC) are one of the two main subtypes of human dendritic cells. pDC, like the classical myeloid dendritic cells (mDC), are able to present antigens to T cells [1], but have a distinctive feature of producing type I interferons (IFN) [2]. pDC are able to secrete IFN-a at levels up to 1000 fold higher than any other blood cell following viral infection [2]. PDC are able to secrete IFN-a at levels up to 1000 fold higher than any other blood cell following viral infection [2]. They recognize pathogens mainly via two pattern recognition receptors: Toll-like receptor 7 (TLR7), which recognizes single-strand RNA, and TLR9, which recognizes unmethylated DNA. The triggering of these receptors induces pDC activation and IFN-a production [3]. Increasing evidence suggests that IFN-a contributes to the generalized pan-immune activation and increased levels of cell apoptosis associated with AIDS progression, and the exact role of pDC in HIV/AIDS pathogenesis remains debatable [6,7,8,9,10]
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