Infection of activated t cells can also be enhanced by first binding hiv1 to dendritic cells dcs 3, 16. Dcsignpositive cells were incubated with gp120coated beads. In this study, we investigated the effects of the interaction between hiv1 gp120 and dcsign on hiv1 production and the pathways involved. Significant reduction of hiv1 transfer upon preincubation with leishmania infantum amastigotes. Hiv 1 capture was completely dc sign dependent, as antibodies against dc sign inhibited hiv 1 infection, and dc sign negative parental thp 1 cells were unable to capture and transmit hiv 1 figure 4a and figure 4b. Hiv1gp120glycoproteininteractingwithdendritic cell. Dcsign, a novel ctype lectin that is expressed in dcs, has recently been shown to bind. Human milk oligosaccharides reduce hiv1gp120 binding to. The combination of antidcsign mabs used for these studies substantially reduced the binding of gp120 to dcsign and inhibited hiv1 uptake by the dcsigntransfectants. Dcsign, a dendritic cellspecific hiv1binding protein. Hiv 1 can bind dendritic cellsurface dc sign or other mannose binding proteins to enhance cd4 t cell infection. Antigen structure affects cellular routing through dcsign. Hiv1 entry across the infants mucosal barrier is partially mediated through binding of the hiv1 surface glycoprotein gp120 to dendritic cellspecific icam3grabbing nonintegrin dcsign on human dendritic cells.
Subsequently we aimed to identify the dc sign binding component through biochemical characterization and mass spectrometry analysis. Cocaine enhances dc to tcell hiv1 transmission by activating. B dcsign binds hiv1 and retains for more than 4 days virus that infects t cells in trans. Indeed, dc sign blockade could significantly prevent dc apoptosis upon coculture with activated cd4 t cells fig. Dcsignmediated transfer of hiv1 is compromised by the. We therefore investigated b cells for a dcsign mediated, trans pathway for hiv1 infection of cd4. Dcsign, a dendritic cellspecific hiv1 binding protein that enhances transinfection of t cells.
Besides its role in dcmediated adhesion processes, dcsign also functions as an antigen receptor that captures and internalises antigens for presentation by dc. Bthp1dcsign cells a and b and primary human immature monocytederived dendritic cells imddcs c and d were first incubated for 1 h at 37c in the absence or presence of l. Hiv 1 interacts with receptors expressed on idc such as ctype lectin receptors clr. Recent studies demonstrate that dc sign is a universal pathogen receptor that also recognizes ebola, cytomegalovirus and mycobacteria. Dcsign interactions with human immunodeficiency virus type 1. Lewis x component in human milk binds dcsign and inhibits. Dc sign is a dendritic cell surface structure which participates in binding and transmission of hiv 1. Dcsignexpressing cells, hiv1 is released from immunecomplexes with the abs 2f5 and. Dc modc can be induced by mtropic hiv 1 r5 strains through binding of gp120 to ccr5 27. A study by hong showed cvn did not inhibit hiv1 jrcsf gp120 binding to the dcsign receptor even at 1 mm hong et al. The results from flowcytometryshowedthatapre19cellsexpresseddcsign and ccr5 but not cd4 and cxcr4 fig. To this end, a dc sign binding elisa, a gp140 trimer competition elisa and hiv 1 capture transfer assays were utilized.
Dcsign is a dcspecific hiv1binding protein preferentially binds to dcsign. Unraveling sugar binding modes to dcsign by employing. Open access modulation of hiv binding to epithelial cells and. Dcsign binding to the hiv envelope protein effectively increases. Mar 03, 2000 dcsign, a dendritic cellspecific hiv1binding protein that enhances transinfection of t cells article pdf available in cell 100. Geijtenbeek tb1, kwon ds, torensma r, van vliet sj, van duijnhoven gc, middel j, cornelissen il, nottet hs, kewalramani vn, littman dr, figdor cg, van kooyk y. Binding of hiv 1 gp120 to dc sign expressed on dc or thp dc sign was also inhibited by the carbohydrate mannan or egta, consistent with previous findings curtis et al. Its unique function is further underscored by its restricted expression on dcs. Dcsign promotes exogenous mhcirestricted hiv1 antigen. Here, for the first time we demonstrate that cocaine induces over expression of dcsign and significantly enhances virus transfer from dcs to tcells by increasing the binding and internalization. Geijtenbeek and colleagues show that early tatindependent hiv1 replication coopts innate receptor signaling by dcsign. Also, the period of infectivity of hiv 1 is increased by several days as a result of dc sign gp120 binding, allowing for efficient transinfection of t cells on dc arrival. Innate signaling by the ctype lectin dcsign dictates immune.
Indeed, dcsign blockade could significantly prevent dc apoptosis upon coculture with activated cd4 t cells fig. Identification of different binding sites in the dendritic cellspecific receptor dc sign for intercellular adhesion molecule 3 and hiv 1 received for publication, december 4, 2001, and in revised form, january 15, 2002. Binding to dcsign can promote hiv and hepatitis c virus to infect tcell from dendritic cells. The journal of biological chemistry 2002 by the american. Hiv 1 gp120 binding to this cell line, thp determine the contribution of each of these receptors dc sign, was also blocked by anti dc sign antibod in this assay system, we examined the effects of antiies, but not by anticd4 figure 1d. Colorectal mucus binds dcsign and inhibits hiv1 trans. Rather, it is captured by the dc and internalized in distinct. Hiv1 interacts with receptors expressed on idc such as ctype lectin receptors clr. Similar to our previous findings, the dc sign mediated infection of the target cells was not due to dc sign binding to icam3. The combination of anti dc sign mabs used for these studies substantially reduced the binding of gp120 to dc sign and inhibited hiv 1 uptake by the dc sign transfectants. It was found that the binding of gp120 with dcsign activated hiv1 5.
Dc sign is a mannose binding ctype lectin expressed on dendritic cells in mucosal tissue including the rectum, uterus, and cervix 21. Similarly, carbohydratesubstituted dendrimers undergo internalization 25, and dcsignexpressing significance dendritic cells dcs express cellsurface lectins that bind to carbohydrates displayed on the surface of pathogens. Dcsign binds to the highly glycosylated hiv envelope env gp120 in a cd4independent. Dc sign is a ctype lectin receptor present on the surface of both macrophages and dendritic cells. Hiv1 can bind dendritic cellsurface dcsign or other mannosebinding proteins to enhance cd4 t cell infection. The reactivation mechanism of latent human immunode. Dcsignligands induce diverent signaling pathways downstream of raf1, indicating that dcsignsignaling is tailored to the pathogen. Also, the period of infectivity of hiv1 is increased by several days as a result of dcsigngp120 binding, allowing for efficient transinfection of t cells on dc arrival. We propose that dcsign efficiently captures hiv1 in the periphery and facilitates its transport to secondary lymphoid organs rich in t cells, to enhance infection. These agents were found to block binding of gp120 beads to the dcsignexpressing cells to the same extent as human milk figure 4, a and b. The dendritic cellspecific intercellular adhesion molecule3grabbing nonintegrin dc sign molecule plays a crucial role in binding hiv 1 through the gp12041 envelope and in transmitting hiv 1 to target cells 9. Geijtenbeek and colleagues show that early tatindependent hiv 1 replication coopts innate receptor signaling by dc sign. Dcsign on b lymphocytes is required for transmission of hiv1 to t lymphocytes giovanna rappocciolo1, paolo piazza1, craig l.
Dc sign, a dendritic cellspecific hiv 1 binding protein that enhances transinfection of t cells. Hiv1 replication requires proviral production of fulllength transcripts. Dcsign increases the affinity of hiv1 envelope glycoprotein. Identification of the optimal dcsign binding site on human. Here, for the first time we demonstrate that cocaine induces over expression of dc sign and significantly enhances virus transfer from dcs to tcells by increasing the binding and internalization. It binds various microorganisms by recognizing highmannosecontaining glycoproteins on their envelopes and especially functions as receptor for several viruses such as hiv and hepatitis c. Dcsign has been implicated as playing an important role in hiv1 transmission and the establishment of infection 4, 6, 2225. The results from flowcytometryshowedthatapre19cellsexpresseddc sign and ccr5 but not cd4 and cxcr4 fig. Antibodies to dc sign inhibit the binding of the hiv 1. Dcsign, a dendritic cellspecific hiv1binding protein that. This dcsign mutant captured hiv1 and infected t cells in trans as efficiently as wildtype dcsign, demonstrating that icam3 binding is not necessary for hiv1 transmission.
Dc sign was originally discovered as a ctype lectin capable of binding the hiv 1 envelope glycoprotein gp120 1 and has since been shown to be important for supporting primary immune responses 2 and enhancing hiv infection of t cells. Laboratory of glyconanotechnology, biofunctional nanomaterial unit, cic biomagune and ciber. The importance of dcsign is, therefore, evident and a full understanding of the recognized mechanism and its di erent ligands remains a matter of interest. To date, dc sign represents a novel class of hiv 1 receptor, because it does not allow viral infection but binds hiv 1 and enhances its infection of t cells in trans. Alternatively, hiv1 can avoid degradation, as virus engagement with ctype lectin receptors clrs, such as dcsign dcspecific icam3grabbing nonintegrin results in trafficking to. Generation of antidcsign monoclonal antibodies capable.
It is extensively reported that dc sign is able to bind the hiv 1 envelope glycoprotein, gp 120, which is exploited by the virus to enhance its infectivity of t cells 11,12. Dcsign, a dendritic cellspecific hiv1 binding protein that enhances transinfection of t cells article pdf available in cell 100. These agents were found to block binding of gp120 beads to the dcsignexpressing cells to. Dc sign on macrophages recognises and binds with high affinity to highmannose type nglycans, a class of pathogen associated molecular patterns pamps commonly found on viruses, bacteria and fungi. After binding of dcsign by hiv1 gp120, transcrip tion elongation by rnapii resulted in fulllength hiv1 transcripts and productive dc.
The lectins griffithsin, cyanovirinn and scytovirin. In contrast, as disease progresses chronically to aids. Dc sign binding to gp120 is a very high affinity interaction and is thus considered to be a critical phase in the entry of hiv 1 15,19,20. Binding of hiv1 gp120 to dcsign promotes ask1 dependent. Similar to our previous findings, the dcsignmediated infection of the target cells was not due to dcsign binding to icam3. Binding of hiv1 gp120 to dcsign expressed on dc or thpdcsign was also inhibited by the carbohydrate mannan or egta, consistent with previous findings curtis et al.
This study provides a basis for the design of drugs that inhibit or alter interactions of dcsign with gp 120 but not with icam3 or vice versa and that have a. Cm was shown to bind dc sign and competes with hiv 1 gp140 trimer for binding. Geijtenbeek tb 1, kwon ds, torensma r, van vliet sj, van duijnhoven gc, middel j, cornelissen il, nottet hs, kewalramani vn, littman dr, figdor cg, van kooyk y. To this end, a dcsign binding elisa, a gp140 trimer competition elisa and hiv1 capture transfer assays were utilized. Dcsign and inhibits hiv1 transfer 78 stronger to dsp than the egta inactivated dcsignfc negative control, indicating that the dcsign binding of dsp was specific. Molecular insights into dcsign binding to selfantigens. An important feature of this trans pathway is that the virus does not establish an efficient, productive infection in these dc. The dendritic cellspecific intercellular adhesion molecule3grabbing nonintegrin dcsign molecule plays a crucial role in binding hiv1 through the gp12041 envelope and in transmitting hiv1 to target cells 9. Using a dc sign binding elisa, the ability of cm to bind dc sign was determined.
Strikingly, hiv1 circumvents processing after binding dcsign. The importance of dc sign is, therefore, evident and a full understanding of the recognized mechanism and its di erent ligands remains a matter of interest. Dcsign by itself does not allow viral fusion in the absence of cd4. Hiv1 exploits innate signaling by tlr8 and dcsign for. It is extensively reported that dcsign is able to bind the hiv1 envelope glycoprotein, gp 120, which is exploited by the virus to enhance its infectivity of t cells 11,12.
Dcsign captures hiv1 and retains longterm infectivity a time course of hiv1 mn gp120 binding to thpdcsign. Cm binds dcsign and blocks its interaction with hiv1 envelope trimer. Beads bound for more than 60 hr as determined by facscan analysis. Binding of hiv1 gp120 to dcsign promotes ask1dependent. Here we show that a subset of b cells in the blood and tonsils of normal donors expressed dc sign, and that this increased after stimulation in vitro with interleukin 4 and cd40 ligand, with enhanced. Jci lewis x component in human milk binds dcsign and.
Dcsign points the way to a novel mechanism for hiv1. Enhancement of infection in vitro of permissive cells that express dc sign was greater for the cd4dependent hiv 1 iiib strain than for the cd4independent strain hiv 1 iiibx 26. Binding to dc sign protects hiv 1 from antigen processing and facilitates its transport to lymphoid tissues, where dc sign promotes hiv 1 infection of t cells. Dcsign on b lymphocytes is required for transmission of. Dc modc can be induced by mtropic hiv1 r5 strains through binding of gp120 to ccr5 27.
Dcsign, a dendritic cellspecific hiv1binding protein that enhances transinfection of t cells article pdf available in cell 100. Cm was shown to bind dcsign and competes with hiv1 gp140 trimer for binding. Hiv1 can bind to the type ii ctype lectin receptor, dendritic cell dcspecific icam3 grabbing nonintegrin dcsign. Gp120 binding with dcsign induces reactivation of hiv1 provirus.
Transfer of hiv1 by b cells via a ctype lectin receptor pathway described for dc could be of signi. Similar to dcsign, lsign also captures the hiv1 virus by binding to the gp120 and promoting the enhancement of t cell infection by hiv1 in trans 17, 34. Gp120 binding with dcsign induces reactivation of hiv1. Keywords ctype lectin dcsign hiv1 innate signaling mycobacteria raf1. Dcsign, a dendritic cellspecific hiv1binding protein that enhances transinfection of t cells. Dcsign is a mannosebinding ctype lectin expressed on dendritic cells in mucosal tissue including the rectum, uterus, and cervix 21. Generation of antidcsign monoclonal antibodies capable of.
Moreover, mutational analysis demonstrates that the hiv1 gp120 binding site in dcsign is different from that of icam3. Dcsign is a dendritic cell surface structure which participates in binding and transmission of hiv1. A study by hong showed cvn did not inhibit hiv 1 jrcsf gp120 binding to the dc sign receptor even at 1 mm hong et al. Mar 20, 2015 cm binds dc sign and blocks its interaction with hiv 1 envelope trimer.
Dcsign was originally discovered as a ctype lectin capable of binding the hiv1 envelope glycoprotein gp120 1 and has since been shown to be important for supporting primary immune responses 2 and enhancing hiv infection of t cells. Binding of hiv 1 bodies against cd4 and dc sign and of a combination 1. Dcsign binding to gp120 is a very high affinity interaction and is thus considered to be a critical phase in the entry of hiv1 15,19,20. Dcsign on b lymphocytes is required for transmission of hiv. The interaction of hiv1 with dcsign can lead to infection of the dcs, or alternatively the virus can be internalized into a trypsinresistant compartment prior to undergoing transfer to its. Hiv1 capture was completely dcsign dependent, as antibodies against dcsign inhibited hiv1 infection, and dcsignnegative parental thp1 cells were unable to capture and transmit hiv1 figure 4a and figure 4b. Open access modulation of hiv binding to epithelial cells.
Similarly, the monodcsign was recently identified as a dcspecific icam3 cytic cell line thp1, which lacks expression of both adhesion receptor that mediates dct cell interactions cd4. Using a dcsign binding elisa, the ability of cm to bind dcsign was determined. Identification of different binding sites in the dendritic cellspecific receptor dcsign for intercellular adhesion molecule 3 and hiv1 received for publication. Role of dcsign and lsign receptors in hiv1 vertical transmission.
Hiv 1 replication requires proviral production of fulllength transcripts. Dcsign is a ctype lectin and has a high affinity for the icam3 molecule. Enhancement of infection in vitro of permissive cells that express dcsign was greater for the cd4dependent hiv1 iiib strain than for the cd4independent strain hiv1 iiibx 26. Uvadare digital academic repository characterization of.