HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

Lambert, Sophie; Bouttier, Manuella; Vassy, Roger; Seigneuret, Michel; Petrow‐Sadowski, Cari; Janvier, Sébastien; Heveker, Nikolaus; Ruscetti, Francis W.; Perret, G; Jones, Kathryn; Pique, Claudine

doi:10.1182/blood-2008-04-150342

Cited by 139 publications

(142 citation statements)

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“…8 pDCs participate in innate and adaptive immunity, 9,10 are located in blood and lymphoid organs, 10,11 and produce up to 1000-fold more interferon-␣ (IFN-␣) than other cell types in response to virus exposure. 12 Three molecules have been characterized for HTLV-1 entry into cells, heparan sulfate proteoglycans 13 and BDCA-4 (also called neuropilin-1) 14 for the initial virus binding to target cells 15 and glucose transporter 1 for the postattachment and the viral fusion. 16,17 Interestingly, BDCA-4 is expressed by mDC and T cells 18,19 but cells expressing the greatest level of BDCA-4 in blood are pDCs, 20 strongly suggesting that HTLV-1 could interact with pDCs.…”

Section: Introductionmentioning

confidence: 99%

Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells

Colisson

Barblu

Gras

et al. 2010

Blood

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A recent report demonstrated that free human T-cell leukemia virus 1 (HTLV-1) could infect plasmacytoid dendritic cells (pDCs). The major role of pDCs is to secrete massive levels of interferon-␣ (IFN-␣) upon virus exposure; however, the induction of IFN-␣ by HTLV-1 remains unknown. We demonstrate here that cellfree HTLV-1 generated a pDC innate immune response by producing massive levels of IFN-␣ that were inhibited by anti-HTLV-1 antibodies. HTLV-1 induced costimulatory molecules and rapid expression of the apoptotic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Furthermore, HTLV-1 stimulated pDC-induced apoptosis of CD4 ؉ T cells expressing DR5, transforming pDCs into IFN-producing killer pDCs. We also observed that an endosomal acidification inhibitor and a Toll-like receptor-7 (TLR7)-specific blocker drastically inhibited pDC response to HTLV-1. Three-dimensional microscopy analysis revealed that unstimulated pDCs were "dormant" IFNproducing killer pDCs with high levels of intracellular TRAIL that could be rapidly mobilized to the surface in response to TLR7 activation. Inhibition of viral degradation in endosomes by chloroquine maintained viral integrity, allowing virus detection by 3-dimensional microscopy. We demonstrate that pDCs respond to cell-free HTLV-1 by producing high levels of IFN-␣ and by mobilizing TRAIL on cell surface after TLR7 triggering. This is the first demonstration of an innate immune response induced by free HTLV-1. (Blood. 2010;115:2177-2185) IntroductionHuman T-cell leukemia virus 1 (HTLV-1), the first characterized human retrovirus, 1 has been identified as the causative agent for adult T-cell leukemia/lymphoma (ATLL) 2,3 and HTLV-1-associated myelopathy/tropical spastic paraparesis, 4 uveitis, and infective dermatitis in children. 5 HTLV-1 virions infect CD4 ϩ T cells, which represent the main target for HTLV-1 infection in peripheral blood. HTLV-1-associated diseases occur after long periods of virus latency. 6 For years it has been thought that unlike other retroviruses, free virions were poorly infectious. 7 However, Jones et al 8 recently reported that freshly isolated myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) are efficiently and productively infected by cell-free HTLV-1. Furthermore, infected mDCs and pDCs were able to transfer virions to autologous CD4 ϩ T cells, clearly demonstrating that cell-free HTLV-1 can be infectious and target DCs. 8 pDCs participate in innate and adaptive immunity, 9,10 are located in blood and lymphoid organs, 10,11 and produce up to 1000-fold more interferon-␣ (IFN-␣) than other cell types in response to virus exposure. 12 Three molecules have been characterized for HTLV-1 entry into cells, heparan sulfate proteoglycans 13 and BDCA-4 (also called neuropilin-1) 14 for the initial virus binding to target cells 15 and glucose transporter 1 for the postattachment and the viral fusion. 16,17 Interestingly, BDCA-4 is expressed by mDC and T cells 18,19 but cells expressing the greatest level of BDCA...

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Section: Introductionmentioning

confidence: 99%

Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells

Colisson

Barblu

Gras

et al. 2010

Blood

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“…Initially, it was described as a regulator of axon collapse and enhancer of angiogenesis. Subsequently, new functions of NRP-1 were characterized and the expanded contemporary view of NRP-1 includes among its functions antigen recognition (3), adhesion via interaction with ␤ integrins (4,5), activation of latent forms of cytokines (6), control of stem cell differentiation (7)(8)(9), and viral infection (10).…”

mentioning

confidence: 99%

Exogenous Recombinant Dimeric Neuropilin-1 Is Sufficient to Drive Angiogenesis

Uniewicz

Fernig

2011

Journal of Biological Chemistry

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Neuropilin-1 (NRP-1) is present on the cell surface of endothelial cells, or as a soluble truncated variant. Membrane NRP-1 is proposed to enhance angiogenesis by promoting the formation of a signaling complex between vascular endothelial growth factor-A 165 (VEGF-A 165 ), VEGF receptor-2 (VEGFR-2) and heparan sulfate, whereas the soluble NRP-1 is thought to act as an antagonist of signaling complex formation. We have analyzed the angiogenic potential of a chimera comprising the entire extracellular NRP-1 region dimerized through an Fc IgG domain and a monomeric truncated NRP-1 variant. Both NRP-1 proteins stimulated tubular morphogenesis and cell migration in HDMECs and HUVECs. Fc rNRP-1 was able to induce VEGFR-2 phosphorylation and expression of the VEGFR-2 specific target, regulator of calcineurin-1 (RCAN1.4). siRNA mediated gene silencing of VEGFR-2 revealed that VEGFR-2 was required for Fc rNRP-1 mediated activation of the intracellular signaling proteins PLC-␥, AKT, and MAPK and tubular morphogenesis. The stimulatory activity was independent of VEGF-A 165 . This was evidenced by depleting the cell culture of exogenous VEGF-A 165 , and using instead for routine culture VEGF-A 121 , which does not interact with NRP-1, and by the inability of VEGF-A sequestering antibodies to inhibit the angiogenic activity of the NRP proteins. Analysis of angiogenesis over a period of 6 days in an in vitro fibroblast/endothelial co-culture model revealed that Fc rNRP-1 could induce endothelial cell tubular morphogenesis. Thus, we conclude that soluble Fc rNRP-1 is a VEGF-A 165 -independent agonist of VEGFR-2 and stimulates angiogenesis in endothelial cells. Neuropilin-1 (NRP-1)4 is a protein known for playing important functions in neural and vascular systems (reviewed in Refs. 1, 2). Initially, it was described as a regulator of axon collapse and enhancer of angiogenesis. Subsequently, new functions of NRP-1 were characterized and the expanded contemporary view of NRP-1 includes among its functions antigen recognition (3), adhesion via interaction with ␤ integrins (4, 5), activation of latent forms of cytokines (6), control of stem cell differentiation (7-9), and viral infection (10).The majority of studies analyzing NRP-1 function in endothelial cells have focused on the role of the native transmembrane protein. NRP-1 was shown to be abundantly expressed in human, mouse, and chick with highest expression in the vascular endothelium, heart and placenta (11-13). Moreover, it was shown that a homozygous deletion of the Nrp1 gene in mice causes embryonic lethality, because of defects in the vessels and general vascularization (14), while exogenously overexpressed NRP-1 led to formation of excess capillaries and hemorrhages (11).Overexpression of NRP-1 has been observed in the tumor microenvironment, where apart from endothelial cells, the tumor cells themselves were shown to express NRP-1 (15, 16). Current knowledge of NRP-1 places it among the key drivers of angiogenesis (17); however, it must be emphasized that the exact me...

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“…HSPG had been showed to bind the HIV-1 protein gp120, therefore facilitating HIV-1 infection. Studies demonstrated that inhibition of HSPG dramatically reduced syncitium formation and infection in CD4+ T cells (Lambert, Bouttier et al, 2009). Furthermore, inhibition of HSPG also reduced infection of dendritic cells.…”

Section: Htlv-1 Receptor Complexmentioning

confidence: 99%

Adult Human T Cell Leukemia

Herbeuval¹

2011

T-Cell Leukemia

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HTLV-1 uses HSPG and neuropilin-1 for entry by molecular mimicry of VEGF165

Cited by 139 publications

References 45 publications

Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells

Free HTLV-1 induces TLR7-dependent innate immune response and TRAIL relocalization in killer plasmacytoid dendritic cells

Exogenous Recombinant Dimeric Neuropilin-1 Is Sufficient to Drive Angiogenesis

Adult Human T Cell Leukemia

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