DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans

Pöhlmann, Stefan; Soilleux, Elizabeth; Baribaud, Frédéric; Leslie, George J.; Morris, Lydia; Trowsdale, John; Lee, Benhur; Coleman, Nicholas; Doms, Robert W.

doi:10.1073/pnas.051631398

Cited by 304 publications

(314 citation statements)

References 38 publications

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“…11 -13,15 However, its tissue distribution and cellular expression are not identical to DC-SIGN. 1,5,11,12,14,15 Notably, immunohistochemical and flow cytometric analyses have failed to detect …”

Section: Discussionmentioning

confidence: 99%

“…Since other investigators were unable to detect DC-SIGNR expression on mucosal cells by immunohistochemistry 5 and, in the present study, we have observed much lower full-length than isoform mRNA copy numbers, we hypothesize that soluble isoforms are the most likely candidates to influence viral transmission. To address this, future studies must establish the presence of soluble DC-SIGNR protein in the tissue and determine the cellular source of DC-SIGNR in the mucosa, which most likely are endothelial 11,12,14 or certain infiltrating DCs, as indicated by our and other studies. 15,16 Most importantly, studies are required that compare the binding avidity for gp120 between DC-SIGNR isoforms generated from the 5-repeat allele and isoforms generated from the 7-repeat allele.…”

Section: Dc-sign(r) Mucosal Transcript Isoforms H Liu Et Almentioning

confidence: 98%

“…DC-SIGNR on isolated DC populations 11,12,15 and the mucosa of vagina and rectum. 5 This has been taken as evidence that DC-SIGNR is not involved in the pathogenesis of sexual HIV-1 transmission.…”

Section: Dc-sign(r) Mucosal Transcript Isoforms H Liu Et Almentioning

confidence: 99%

“…11 -13 Immunohistochemical staining revealed that expression of DC-SIGNR was distinct from DC-SIGN and occurred predominantly in the endothelia of the liver, lymph nodes, and placenta. 11,12,14 In addition, some studies demonstrated mRNA encoding DC-SIGNR also in monocyte-derived DCs, albeit at a significantly lower level than DC-SIGN mRNA. 11,15,16 Both DC-SIGN and DC-SIGNR are organized into three domains: an N-terminal cytoplasmic domain, a repeat region containing seven repeats of a 23 amino-acid sequence, and a C-terminal domain with homology to C-type lectins.…”

Section: Introductionmentioning

confidence: 99%

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Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms

et al. 2005

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The repeat region of DC-SIGNR (CD209L) is polymorphic on the genomic level, and, in a separate study, we observed a correlation between the DC-SIGNR genotype and HIV-1 susceptibility during sexual contact. However, previous investigations using immunohistochemistry failed to detect membrane-bound DC-SIGNR on cells in the genital and rectal mucosa. We therefore explored the presence of DC-SIGNR in these compartments with a more sensitive limiting dilution RT-PCR, which also allowed for quantification of alternatively spliced mRNA isoforms. DC-SIGN (CD209) and DC-SIGNR mRNA transcript isoforms were found in all 12 vaginal and two rectal biopsies obtained from 14 healthy individuals. For DC-SIGNR, we detected significantly more isoform than full-length transcripts (mean copy numbers/lg RNA: 602 vs 26; P ¼ 0.0009). Four mucosal samples lacked full-length DC-SIGNR transcripts entirely. Cloning and sequencing of DC-SIGNR mRNA in three additional individuals revealed a diverse repertoire of DC-SIGNR isoforms, many of which encoded for proteins predicted to be soluble and secreted. Indeed, in one vaginal sample, we detected only soluble isoforms. In conjunction with our prior observation that the DC-SIGNR genotype has an effect on HIV-1 transmission in vivo, these findings emphasize that DC-SIGNR, in addition to DC-SIGN, should be considered as a cofactor in sexual HIV-1 transmission. Soluble isoforms, in particular, may modulate the efficiency of viral transmission and dissemination.

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Section: Discussionmentioning

confidence: 99%

Section: Dc-sign(r) Mucosal Transcript Isoforms H Liu Et Almentioning

confidence: 98%

Section: Dc-sign(r) Mucosal Transcript Isoforms H Liu Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms

et al. 2005

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“…Several receptors have been reported to facilitate HIV-1 entry into CD4-negative cells. Specifically, galactosyl ceramide (34,35,95), adhesion molecules such as ICAM-1 and LFA-1 (27,28,72), C-type lectins such as DC-SIGN, DC-SIGNR, langerin, and the mannose receptor (12,30,66,87), and proteoglycans containing chondroitin or heparan sulfate proteoglycan chains (CSPGs or HSPGs, respectively) (8,15,53,75,94) have all been shown to promote HIV-1 attachment and/or entry into cells that lack CD4. To date, there is no demonstration that these receptors are capable of mediating fusion between viral and cellular membranes.…”

mentioning

confidence: 99%

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

105

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As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

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C ‐Type Animal Lectins

Weis

2004

Handbook of Metalloproteins

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C‐type animal lectins are a large family of carbohydrate‐binding proteins, which display a strict dependence on Ca 2+ for their activity. Family members contain one or more carbohydrate‐recognition domains (CRDs) approximately 110 to 150 amino acids in length. Structural analysis of these proteins reveals that binding to sugars is mediated by direct coordination of a conserved Ca 2+ . The Ca 2+ dependence of sugar binding is exploited in a number of family members that serve as cell surface endocytic receptors, where the acidic environment of the endosome causes changes in Ca 2+ coordination and release of the bound ligand.

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DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans

Cited by 304 publications

References 38 publications

Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms

Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

C ‐Type Animal Lectins

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