Plasmacytoid dendritic cells accumulate in spleens from chronically HIV-infected patients but barely participate in interferon-alpha expression.
ABSTRACT We characterized the localization, phenotype, and some functions of plasmacytoid dendritic cells (pDCs) in the human spleen. pDCs were localized in the marginal zone and the periarteriolar region. Some were also found in the red pulp. pDCs were immature by phenotypic labeling, consistently with their capacity to internalize Dextran in a functional assay. In spleens from HIV-infected patients with thrombocytopenic purpura, these characteristics were unaffected. However, an accumulation of pDCs, but not myeloid dendritic cells (mDCs), was observed in some HIV+ patients, correlating with high proviral loads. Moreover, although undetectable in most HIV- patients, interferon-alpha (IFN-alpha) production was evidenced in situ and by flow cytometry in most HIV+ patients. IFN-alpha was located in the marginal zone. Surprisingly, IFN-alpha colocalized only with few pDCs, but rather with other cells, including T and B lymphocytes, mDCs, and macrophages. Therefore, pDCs accumulated in spleens from HIV+ patients with high proviral loads, but they did not seem to be the main IFN-alpha producers.
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ABSTRACT: The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.PLoS Pathogens 07/2014; 10(7):e1004291. DOI:10.1371/journal.ppat.1004291 · 8.06 Impact Factor
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ABSTRACT: Abstract Lentivirus infections are characterized by a dramatic loss of mucosal CD4(+) T cells, breakdown of the gut mucosa, and subsequent chronic immune activation. Residual immune activation persists even in patients controlling virus replication and remains a significant source of ongoing disease morbidities, but the causes are unclear. Plasmacytoid dendritic cells (pDCs), primary producers of interferon (IFN)-α, have been previously shown to be depleted from peripheral blood of HIV patients and simian immunodeficiency virus (SIV)-infected macaques, and most recently have been shown to accumulate in the gut mucosa. Although previous work has shown that pDC frequencies can be reduced in the circulation of HIV-1 Elite Controllers, it is unknown if gut-homing also occurs. In this new study we found that during progressive HIV-1 infection pDCs were depleted in peripheral blood compared to seronegative controls, and, correlating with plasma viremia, the remaining pDCs upregulated the gut-homing marker, α4β7. Even in HIV-1 Elite Controllers pDCs were significantly reduced in blood and α4β7 expression was still significantly upregulated compared to seronegative controls. Interestingly, pDC trafficking to the gut was associated with increased Ki67 and HLA-DR on circulating CD4(+) and CD8(+) T cells. Overall, these data suggest that gut trafficking of pDCs is independent of virus replication and could be mediated by alternative mechanisms, which in turn could contribute to residual immune activation in HIV-1 Elite Controllers.AIDS Research and Human Retroviruses 11/2014; 30(12). DOI:10.1089/aid.2014.0174 · 2.46 Impact Factor
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ABSTRACT: Chronic immune activation (IA) is considered as the driving force of CD4+ T cell depletion and AIDS. Fundamental clues in the mechanisms that regulate IA could lie in natural hosts of SIV, such as African green monkeys (AGMs). Here we investigated the role of innate immune cells and IFN-α in the control of IA in AGMs. AGMs displayed significant NK cell activation upon SIVagm infection, which was correlated with the levels of IFN-α. Moreover, we detected cytotoxic NK cells in lymph nodes during the early acute phase of SIVagm infection. Both plasmacytoid and myeloid dendritic cell (pDC and mDC) homing receptors were increased, but the maturation of mDCs, in particular of CD16+ mDCs, was more important than that of pDCs. Monitoring of 15 cytokines showed that those, which are known to be increased early in HIV-1/SIVmac pathogenic infections, such as IL-15, IFN-α, MCP-1 and CXCL10/IP-10, were significantly increased in AGMs as well. In contrast, cytokines generally induced in the later stage of acute pathogenic infection, such as IL-6, IL-18 and TNF-α, were less or not increased, suggesting an early control of IA. We then treated AGMs daily with high doses of IFN-α from day 9 to 24 post-infection. No impact was observed on the activation or maturation profiles of mDCs, pDCs and NK cells. There was also no major difference in T cell activation or interferon-stimulated gene (ISG) expression profiles and no sign of disease progression. Thus, even after administration of high levels of IFN-α during acute infection, AGMs were still able to control IA, showing that IA control is independent of IFN-α levels. This suggests that the sustained ISG expression and IA in HIV/SIVmac infections involves non-IFN-α products.PLoS Pathogens 07/2014; 10(7):e1004241. DOI:10.1371/journal.ppat.1004241 · 8.06 Impact Factor