Evidence of dysregulation of dendritic cells in primary HIV infection

Sabado, Rachel Lubong; O’Brien, Meagan P.; Subedi, Abhignya; Li, Qin; Hu, Nan; Taylor, E. G.; Dibben, Oliver; Stacey, Andrea; Fellay, Jacques; Shianna, Kevin V.; Siegal, Frederick P.; Shodell, Michael; Shah, K M; Larsson, Marie; Lifson, Jeffrey D.; Nádas, Arthur; Marmor, Michael; Hutt, Richard; Margolis, David M.; Garmon, Donald; Markowitz, Martin; Valentine, Fred; Borrow, Persephone; Bhardwaj, Nina

doi:10.1182/blood-2010-03-273763

Cited by 153 publications

(191 citation statements)

References 50 publications

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“…These data bring the first biological evidence to our knowledge of an interplay between AGEs and HIV-1 infection of MDDCs in vitro. However, further experiments will be necessary to determine whether accumulated AGEs in the blood of diabetic patients have the same inhibitory effect on HIV infection of primary myeloid DCs, which also express the HIV-1 receptors CD4/ CCR5/CXCR4 and are susceptible to infection by HIV-1 (61).…”

Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Nasreddine

Borde

Gozlan

et al. 2011

The Journal of Immunology

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Highly active antiretroviral therapy is associated with carbohydrate metabolic alterations that may lead to diabetes. One consequence of hyperglycemia is the formation of advanced glycation end products (AGEs) that are involved in diabetes complications. We investigated the impact of AGEs on the infection of monocyte-derived dendritic cells (MDDCs) by HIV-1 and the ability of MDDCs to transmit the virus to T cells. We showed that AGEs could inhibit infection of MDDCs with primary R5-tropic HIV-1Ba-L by up to 85 ± 9.2% and with primary X4-tropic HIV-1VN44 by up to 60 ± 8.5%. This inhibitory effect of AGEs was not prevented by a neutralizing anti-receptor for advanced glycation end products (anti-RAGE) Ab, demonstrating a RAGE-independent mechanism. Moreover, AGEs inhibited by 70–80% the transmission in trans of the virus to CD4 T cells. Despite the inhibitory effect of AGEs on both MDDC infection and virus transmission in trans, no inhibition of virus attachment to cell membrane was observed, confirming that attachment and transmission of the virus involve independent mechanisms. The inhibitory effect of AGEs on infection was associated with a RAGE-independent downregulation of CD4 at the cell membrane and by a RAGE-dependent repression of the CXCR4 and CCR5 HIV-1 receptors. AGEs induce the secretion of proinflammatory cytokines IL-6, TNF-α, and IL-12, but not RANTES or MIP-1α, and did not lead to MDDC maturation as demonstrated by the lack of expression of the CD83 molecule. Taken together, our results suggest that AGEs can play an inhibiting role in HIV-1 infection in patients who accumulate circulating AGEs, including patients treated with protease inhibitors that developed diabetes.

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Section: Discussionmentioning

confidence: 99%

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Nasreddine

Borde

Gozlan

et al. 2011

The Journal of Immunology

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“…Classically, pDCs are described as being refractory to IFN-α production upon repeated stimulation with synthetic TLR7 or TLR9 agonists, which is thought to be a protective mechanism against excessive immune activation (19,20). To our knowledge, pDC tolerance to repeated stimulation with HIV, a TLR7 agonist, has never been evaluated, but we and others have observed that pDCs from HIV-infected subjects can be stimulated ex vivo with HIV to produce IFN-α (21,22). Because pDCs derived from HIV-infected subjects have been exposed to HIV in vivo, we reasoned that HIV may uniquely allow for repeated stimulation of pDCs.…”

Section: Introductionmentioning

confidence: 98%

Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α–producing and partially matured phenotype

O’Brien¹,

Manches²,

Sabado³

et al. 2011

J. Clin. Invest.

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Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-α and to activate adaptive immune responses. Although IFN-α inhibits HIV-1 replication in vitro, the production of IFN-α by HIVactivated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-α production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-α production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-α/β receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-α pathway but weak activation of the NF-κB pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-α-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-α-secreting phenotype.

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“…HIV-1 infection induces CD4 + T lymphocyte depletion and AIDS. It induces mDC and pDC depletion, at least in patients with high viral loads (25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Among DC subsets, CD141 + mDC show the deepest attrition (35).…”

Section: Ouse Cd8amentioning

confidence: 99%

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

Dutertre¹,

Jourdain²,

Rancez³

et al. 2014

The Journal of Immunology

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In mice, CD8α+ myeloid dendritic cells (mDC) optimally cross-present Ags to CD8+ T cells and respond strongly to TLR3 ligands. Although equivalent DC have been identified by comparative genomic analysis and functional studies in humans as XCR1+CD141 (BDCA-3)+Clec9A+cell adhesion molecule 1+ mDC, and in sheep as CD26+ mDC, these cells remained elusive in nonhuman primates. To remedy this situation, we delineated precisely DC and monocyte populations by 12-color flow cytometry and transcriptomic analyses in healthy rhesus macaques. We identified a new mDC population, with strong phenotypic and transcriptional homology to human CD141+ and murine CD8α+ mDC, including XCR1 membrane expression as a conserved specific marker. In contrast, high CD11c expression was not characteristic of mDC in macaques, but of CD16+ monocytes. Like their human and murine homologs, simian XCR1+ mDC had much stronger responses to TLR3 stimulation than other myeloid cells. The importance of this new mDC population was tested in SIVmac251 infection, the most relevant animal model for pathogenic HIV-1 infection and vaccination. This population increased sharply and transiently during acute infection, but was reduced in blood and spleen during advanced disease. The identification of XCR1+ mDC in rhesus macaques opens new avenues for future preclinical vaccinal studies and highlights XCR1 as a prime candidate for targeted vaccine delivery.

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Evidence of dysregulation of dendritic cells in primary HIV infection

Cited by 153 publications

References 50 publications

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α–producing and partially matured phenotype

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

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