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Jeffrey D Esko - One of the best experts on this subject based on the ideXlab platform.
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Heparan Sulfate Proteoglycans fine-tune macrophage inflammation via IFN-β
Cytokine, 2015Co-Authors: Philip L.s.m. Gordts, Jeffrey D EskoAbstract:Macrophages are important mediators of diseases associated with metabolic inflammation such as obesity and atherosclerosis. In this Stimulus we discuss recent findings showing that Heparan Sulfate Proteoglycans on macrophages serve as an important inflammatory rheostat. This observation has significant implications as the degree of macrophage proteoglycan sulfation can determine and possibly predict disease outcomes of metabolic inflammatory disorders.
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Heparan Sulfate Proteoglycans
Cold Spring Harbor Perspectives in Biology, 2011Co-Authors: Stephane Sarrazin, William C Lamanna, Jeffrey D EskoAbstract:Heparan Sulfate Proteoglycans (HSPGs) are glycoproteins, with the common characteristic of containing one or more covalently attached Heparan Sulfate (HS) chains, a type of glycosaminoglycan (GAG) (Esko et al. 2009). Cells elaborate a relatively small set of HSPGs (∼17) that fall into three groups according to their location: membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored Proteoglycans (glypicans), the secreted extracellular matrix HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin (Table 1). Much of the early work in the field concentrated on composition (size, chain number, and structure of the HS chains), biosynthesis, and binding properties of the chains. In 1985, the first somatic cell mutants altered in HSPG expression were identified (Esko et al. 1985), which allowed functional studies in the context of a cell culture model (Zhang et al. 2006). A decade later, the first HSPG mutants in a model organism (Drosophila melanogaster) were identified (Rogalski et al. 1993; Nakato et al. 1995; Hacker et al. 1997; Bellaiche et al. 1998; Lin et al. 1999), which was followed by identification of mutants in nematodes, tree frogs, zebrafish, and mice (Tables 2 and and3).3). HS is evolutionarily ancient and its composition has remained relatively constant from Hydra to humans (Yamada et al. 2007; Lawrence et al. 2008). Table 1. Heparan Sulfate Proteoglycans Table 2. Mutants altered in HSPG core proteins Table 3. Mouse mutants altered in HS biosynthesis Figure 1 shows in pictorial form many of the systems in which HSPGs participate. HSPGs are present in basement membranes (perlecan, agrin, and collagen XVIII), where they collaborate with other matrix components to define basement membrane structure and to provide a matrix for cell migration. HSPGs are found in secretory vesicles, most notably serglycin, which plays a role in packaging granular contents, maintaining proteases in an active state, and regulating various biological activities after secretion such as coagulation, host defense, and wound repair. HSPGs can bind cytokines, chemokines, growth factors, and morphogens, protecting them against proteolysis. These interactions provide a depot of regulatory factors that can be liberated by selective degradation of the HS chains. They also facilitate the formation of morphogen gradients essential for cell specification during development and chemokine gradients involved in leukocyte recruitment and homing. HSPGs can act as receptors for proteases and protease inhibitors regulating their spatial distribution and activity. Membrane Proteoglycans cooperate with integrins and other cell adhesion receptors to facilitate cell-ECM attachment, cell–cell interactions, and cell motility. Membrane HSPGs act as coreceptors for various tyrosine kinase-type growth factor receptors, lowering their activation threshold or changing the duration of signaling reactions. Membrane HSPGs act as endocytic receptors for clearance of bound ligands, which is especially relevant in lipoprotein metabolism in the liver and perhaps in the formation of morphogen gradients during development. Figure 1. HSPGs have multiple activities in cells and tissues. (Adapted from Bishop et al. 2007; reprinted with permission from Nature Publishing Group © 2007.) This article is divided into 10 subsections. The first three are written for investigators outside the field who may need some background information on the diversity of HSPGs and the interactions that occur with protein ligands. The subsequent sections describe seven systems that illustrate general principles or ideas that have undergone a significant shift over the last decade. Because of space limitations not all subjects can be considered or treated in appropriate depth and therefore the reader is referred to excellent recent review articles (Tkachenko et al. 2005; Bulow and Hobert 2006; Bishop et al. 2007; Lamanna et al. 2007; Bix and Iozzo 2008; Filmus et al. 2008; Ori et al. 2008; Rodgers et al. 2008; Sanderson and Yang 2008; Iozzo et al. 2009; Couchman 2010).
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Heparan Sulfate Proteoglycans
Cold Spring Harbor perspectives in biology, 2011Co-Authors: Stephane Sarrazin, William C Lamanna, Jeffrey D EskoAbstract:Heparan Sulfate Proteoglycans are found at the cell surface and in the extracellular matrix, where they interact with a plethora of ligands. Over the last decade, new insights have emerged regarding the mechanism and biological significance of these interactions. Here, we discuss changing views on the specificity of protein-Heparan Sulfate binding and the activity of HSPGs as receptors and coreceptors. Although few in number, Heparan Sulfate Proteoglycans have profound effects at the cellular, tissue, and organismal level.
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Hepatic Heparan Sulfate Proteoglycans and Endocytic Clearance of Triglyceride-Rich Lipoproteins
Progress in molecular biology and translational science, 2010Co-Authors: Erin M. Foley, Jeffrey D EskoAbstract:Hypertriglyceridemia, characterized by the accumulation of triglyceride-rich lipoproteins in the blood, affects 10-20% of the population in western countries and increases the risk of atherosclerosis, coronary artery disease, and pancreatitis. The etiology of hypertriglyceridemia is complex, and much interest exists in identifying and characterizing the biological and environmental factors that affect the synthesis and turnover of plasma triglycerides. Genetic studies in mice have recently identified that Heparan Sulfate Proteoglycans are a class of receptors that mediate the clearance of triglyceride-rich lipoproteins in the liver. Heparan Sulfate Proteoglycans are expressed by endothelial cells that line the hepatic sinusoids and the underlying hepatocytes, and are present in the perisinusoidal space (space of Disse). This chapter discusses the dependence of lipoprotein binding on Heparan Sulfate structure and the identification of hepatocyte syndecan-1 as the primary proteoglycan that mediates triglyceride-rich lipoprotein clearance.
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Heparan Sulfate Proteoglycans and triglyceride-rich lipoprotein metabolism.
Current opinion in lipidology, 2008Co-Authors: Joseph R. Bishop, Kristin I. Stanford, Jeffrey D EskoAbstract:PURPOSE OF REVIEW Clearance of triglyceride-rich lipoprotein remnants by the liver is a key step in preventing hypertriglyceridemia, an independent risk factor for cardiovascular disease. We review recent genetic evidence that Heparan Sulfate Proteoglycans work in concert with the LDL receptor in the liver to facilitate binding and clearance of both triglyceride and cholesterol-rich lipoproteins from the circulation. RECENT FINDINGS Partial reduction of sulfation of liver Heparan Sulfate using the Cre-loxP system caused accumulation of hepatic and dietary triglyceride-rich lipoprotein particles due to delayed clearance. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol and triglyceride-rich particles compared with mice lacking only LDL receptors. These findings provide the first genetic evidence that hepatic Heparan Sulfate Proteoglycans play a central role in the clearance of lipoproteins by the liver and work independently of LDL receptors. SUMMARY A role for hepatocyte Heparan Sulfate in lipoprotein metabolism has now been genetically established in mice. Given this finding, mild, but clinically relevant, hyperlipidemias in human patients may be a result of alterations in Heparan Sulfate structure or possible genetic polymorphisms in the relevant biosynthetic genes.
Photini Sinnis - One of the best experts on this subject based on the ideXlab platform.
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Heparan Sulfate Proteoglycans provide a signal to plasmodium sporozoites to stop migrating and productively invade host cells
Cell Host & Microbe, 2007Co-Authors: Alida Coppi, Joseph R. Bishop, Jeffrey D Esko, Rita Tewari, Brandy L Bennett, Roger Lawrence, Oliver Billker, Photini SinnisAbstract:Malaria infection is initiated when Anopheles mosquitoes inject Plasmodium sporozoites into the skin. Sporozoites subsequently reach the liver, invading and developing within hepatocytes. Sporozoites contact and traverse many cell types as they migrate from skin to liver; however, the mechanism by which they switch from a migratory mode to an invasive mode is unclear. Here, we show that sporozoites of the rodent malaria parasite Plasmodium berghei use the sulfation level of host Heparan Sulfate Proteoglycans (HSPGs) to navigate within the mammalian host. Sporozoites migrate through cells expressing low-Sulfated HSPGs, such as those in skin and endothelium, while highly Sulfated HSPGs of hepatocytes activate sporozoites for invasion. A calcium-dependent protein kinase is critical for the switch to an invasive phenotype, a process accompanied by proteolytic cleavage of the sporozoite's major surface protein. These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry.
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the binding of the circumsporozoite protein to cell surface Heparan Sulfate Proteoglycans is required for plasmodium sporozoite attachment to target cells
Journal of Biological Chemistry, 2001Co-Authors: Consuelo Pinzonortiz, Jennifer F Friedman, Jeffrey D Esko, Photini SinnisAbstract:Abstract The major surface protein of malaria sporozoites, the circumsporozoite protein, binds to Heparan Sulfate Proteoglycans on the surface of hepatocytes. It has been proposed that this binding event is responsible for the rapid and specific localization of sporozoites to the liver after their injection into the skin by an infected anopheline mosquito. Previous in vitro studies performed under static conditions have failed to demonstrate a significant role for Heparan Sulfate Proteoglycans during sporozoite invasion of cells. We performed sporozoite attachment and invasion assays under more dynamic conditions and found a dramatic decrease in sporozoite attachment to cells in the presence of heparin. In contrast to its effect on attachment, heparin does not appear to have an effect on sporozoite invasion of cells. When substituted heparins were used as competitive inhibitors of sporozoite attachment, we found that sulfation of the glycosaminoglycan chains at both the N- and O-positions was important for sporozoite adhesion to cells. We conclude that the binding of the circumsporozoite protein to hepatic Heparan Sulfate Proteoglycans is likely to function during sporozoite attachment in the liver and that this adhesion event depends on the Sulfated glycosaminoglycan chains of the Proteoglycans.
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malaria circumsporozoite protein binds to Heparan Sulfate Proteoglycans associated with the surface membrane of hepatocytes
Journal of Experimental Medicine, 1993Co-Authors: Ute Frevert, Photini Sinnis, Bela Takacs, Carla Cerami, Wayne G. Shreffler, Victor NussenzweigAbstract:During feeding by infected mosquitoes, malaria sporozoites are injected into the host's bloodstream and enter hepatocytes within minutes. The remarkable target cell specificity of this parasite may be explained by the presence of receptors for the region II-plus of the circumsporozoite protein (CS) on the basolateral domain of the plasma membrane of hepatocytes. We have now identified these receptors as Heparan Sulfate Proteoglycans (HSPG). The binding of CS to the receptors is abolished by heparitinase treatment, indicating that the recognition of region II-plus is via the glycosaminoglycan chains. We have purified and partially characterized the CS-binding HSPGs from HepG2 cells. They have a molecular weight of 400,000-700,000, are tightly associated with the plasma membrane, and are released from the cell surface by very mild trypsinization, a property which the CS receptors share with the syndecan family of Proteoglycans.
Joseph R. Bishop - One of the best experts on this subject based on the ideXlab platform.
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Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis
Arteriosclerosis thrombosis and vascular biology, 2012Co-Authors: Sébastien Le Jan, Joseph R. Bishop, Makoto Hayashi, Zsolt Kasza, Inger Eriksson, Irene Weibrecht, Johan Heldin, Katarina Holmborn, Lars Jakobsson, Ola SöderbergAbstract:OBJECTIVE: Heparan Sulfate Proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between Heparan Sulfate prote ...
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Heparan Sulfate Proteoglycans and triglyceride-rich lipoprotein metabolism.
Current opinion in lipidology, 2008Co-Authors: Joseph R. Bishop, Kristin I. Stanford, Jeffrey D EskoAbstract:PURPOSE OF REVIEW Clearance of triglyceride-rich lipoprotein remnants by the liver is a key step in preventing hypertriglyceridemia, an independent risk factor for cardiovascular disease. We review recent genetic evidence that Heparan Sulfate Proteoglycans work in concert with the LDL receptor in the liver to facilitate binding and clearance of both triglyceride and cholesterol-rich lipoproteins from the circulation. RECENT FINDINGS Partial reduction of sulfation of liver Heparan Sulfate using the Cre-loxP system caused accumulation of hepatic and dietary triglyceride-rich lipoprotein particles due to delayed clearance. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol and triglyceride-rich particles compared with mice lacking only LDL receptors. These findings provide the first genetic evidence that hepatic Heparan Sulfate Proteoglycans play a central role in the clearance of lipoproteins by the liver and work independently of LDL receptors. SUMMARY A role for hepatocyte Heparan Sulfate in lipoprotein metabolism has now been genetically established in mice. Given this finding, mild, but clinically relevant, hyperlipidemias in human patients may be a result of alterations in Heparan Sulfate structure or possible genetic polymorphisms in the relevant biosynthetic genes.
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Heparan Sulfate Proteoglycans provide a signal to plasmodium sporozoites to stop migrating and productively invade host cells
Cell Host & Microbe, 2007Co-Authors: Alida Coppi, Joseph R. Bishop, Jeffrey D Esko, Rita Tewari, Brandy L Bennett, Roger Lawrence, Oliver Billker, Photini SinnisAbstract:Malaria infection is initiated when Anopheles mosquitoes inject Plasmodium sporozoites into the skin. Sporozoites subsequently reach the liver, invading and developing within hepatocytes. Sporozoites contact and traverse many cell types as they migrate from skin to liver; however, the mechanism by which they switch from a migratory mode to an invasive mode is unclear. Here, we show that sporozoites of the rodent malaria parasite Plasmodium berghei use the sulfation level of host Heparan Sulfate Proteoglycans (HSPGs) to navigate within the mammalian host. Sporozoites migrate through cells expressing low-Sulfated HSPGs, such as those in skin and endothelium, while highly Sulfated HSPGs of hepatocytes activate sporozoites for invasion. A calcium-dependent protein kinase is critical for the switch to an invasive phenotype, a process accompanied by proteolytic cleavage of the sporozoite's major surface protein. These findings explain how sporozoites retain their infectivity for an organ that is far from their site of entry.
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liver Heparan Sulfate Proteoglycans mediate clearance of triglyceride rich lipoproteins independently of ldl receptor family members
Journal of Clinical Investigation, 2007Co-Authors: Jennifer M Macarthur, Joseph R. Bishop, Kristin I. Stanford, André Bensadoun, Lianchun Wang, Joseph L Witztum, Jeffrey D EskoAbstract:We examined the role of hepatic Heparan Sulfate in triglyceride-rich lipoprotein metabolism by inactivating the biosynthetic gene GlcNAc N-deacetylase/N-sulfotransferase 1 (Ndst1) in hepatocytes using the Cre-loxP system, which resulted in an approximately 50% reduction in sulfation of liver Heparan Sulfate. Mice were viable and healthy, but they accumulated triglyceride-rich lipoprotein particles containing apoB-100, apoB-48, apoE, and apoCI-IV. Compounding the mutation with LDL receptor deficiency caused enhanced accumulation of both cholesterol- and triglyceride-rich particles compared with mice lacking only LDL receptors, suggesting that Heparan Sulfate participates in the clearance of cholesterol-rich lipoproteins as well. Mutant mice synthesized VLDL normally but showed reduced plasma clearance of human VLDL and a corresponding reduction in hepatic VLDL uptake. Retinyl ester excursion studies revealed that clearance of intestinally derived lipoproteins also depended on hepatocyte Heparan Sulfate. These findings show that under normal physiological conditions, hepatic Heparan Sulfate Proteoglycans play a crucial role in the clearance of both intestinally derived and hepatic lipoprotein particles.
Stephan Urban - One of the best experts on this subject based on the ideXlab platform.
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Hepatitis B virus infection initiates with a large surface protein-dependent binding to Heparan Sulfate Proteoglycans.
Hepatology, 2007Co-Authors: Andreas Schulze, Philippe Gripon, Stephan UrbanAbstract:Contrary to many other viruses, the initial steps of the hepatitis B virus (HBV) infection, including attachment to hepatocytes, specific receptor interactions, and membrane fusion, are unsolved. Using HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cell-surface-associated Heparan Sulfate Proteoglycans. Binding to GAGs requires the integrity of the pre-S domain as a part of the large (L-) viral envelope protein. HBV infection was abrogated by incubation of virions with heparin, but not the structurally related GAGs chondroitin Sulfate A, B, and C. Infection was also abolished by suramin, a known inhibitor of duck hepatitis B virus infection or highly Sulfated dextran Sulfate. Polycationic substances such as poly-L-lysine, polybrene, and protamine also prevented infection, however, by addressing cellular components. Enzymatic removal of defined acidic carbohydrate structures from the cell surface using heparinase I/III or the obstruction of GAG synthesis by sodium chlorate inhibited HBV infection of HepaRG cells and, moreover, led to a reduction of HBV cell surface binding sites. The biochemical analysis showed selective binding of L-protein-enriched viral particles (virions or filaments) to heparin. GAG-dependent binding of HBV was improved by polyethylene glycol, a substance that specifically enhances HBV infection. Conclusion: HBV infection requires the initial attachment to the carbohydrate side chains of hepatocyte-associated Heparan Sulfate Proteoglycans as attachment receptors. This interaction initializes the multistep entry process of HBV and cannot be bypassed by alternative routes.
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hepatitis b virus infection initiates with a large surface protein dependent binding to Heparan Sulfate Proteoglycans
Hepatology, 2007Co-Authors: Andreas Schulze, Philippe Gripon, Stephan UrbanAbstract:Contrary to many other viruses, the initial steps of the hepatitis B virus (HBV) infection, including attachment to hepatocytes, specific receptor interactions, and membrane fusion, are unsolved. Using HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cell-surface–associated Heparan Sulfate Proteoglycans. Binding to GAGs requires the integrity of the pre-S domain as a part of the large (L-) viral envelope protein. HBV infection was abrogated by incubation of virions with heparin, but not the structurally related GAGs chondroitin Sulfate A, B, and C. Infection was also abolished by suramin, a known inhibitor of duck hepatitis B virus infection or highly Sulfated dextran Sulfate. Polycationic substances such as poly-L-lysine, polybrene, and protamine also prevented infection, however, by addressing cellular components. Enzymatic removal of defined acidic carbohydrate structures from the cell surface using heparinase I/III or the obstruction of GAG synthesis by sodium chlorate inhibited HBV infection of HepaRG cells and, moreover, led to a reduction of HBV cell surface binding sites. The biochemical analysis showed selective binding of L-protein–enriched viral particles (virions or filaments) to heparin. GAG-dependent binding of HBV was improved by polyethylene glycol, a substance that specifically enhances HBV infection. Conclusion: HBV infection requires the initial attachment to the carbohydrate side chains of hepatocyte-associated Heparan Sulfate Proteoglycans as attachment receptors. This interaction initializes the multistep entry process of HBV and cannot be bypassed by alternative routes. (HEPATOLOGY 2007;46:1759–1768.)
Andreas Schulze - One of the best experts on this subject based on the ideXlab platform.
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Hepatitis B virus infection initiates with a large surface protein-dependent binding to Heparan Sulfate Proteoglycans.
Hepatology, 2007Co-Authors: Andreas Schulze, Philippe Gripon, Stephan UrbanAbstract:Contrary to many other viruses, the initial steps of the hepatitis B virus (HBV) infection, including attachment to hepatocytes, specific receptor interactions, and membrane fusion, are unsolved. Using HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cell-surface-associated Heparan Sulfate Proteoglycans. Binding to GAGs requires the integrity of the pre-S domain as a part of the large (L-) viral envelope protein. HBV infection was abrogated by incubation of virions with heparin, but not the structurally related GAGs chondroitin Sulfate A, B, and C. Infection was also abolished by suramin, a known inhibitor of duck hepatitis B virus infection or highly Sulfated dextran Sulfate. Polycationic substances such as poly-L-lysine, polybrene, and protamine also prevented infection, however, by addressing cellular components. Enzymatic removal of defined acidic carbohydrate structures from the cell surface using heparinase I/III or the obstruction of GAG synthesis by sodium chlorate inhibited HBV infection of HepaRG cells and, moreover, led to a reduction of HBV cell surface binding sites. The biochemical analysis showed selective binding of L-protein-enriched viral particles (virions or filaments) to heparin. GAG-dependent binding of HBV was improved by polyethylene glycol, a substance that specifically enhances HBV infection. Conclusion: HBV infection requires the initial attachment to the carbohydrate side chains of hepatocyte-associated Heparan Sulfate Proteoglycans as attachment receptors. This interaction initializes the multistep entry process of HBV and cannot be bypassed by alternative routes.
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hepatitis b virus infection initiates with a large surface protein dependent binding to Heparan Sulfate Proteoglycans
Hepatology, 2007Co-Authors: Andreas Schulze, Philippe Gripon, Stephan UrbanAbstract:Contrary to many other viruses, the initial steps of the hepatitis B virus (HBV) infection, including attachment to hepatocytes, specific receptor interactions, and membrane fusion, are unsolved. Using HepaRG cells as an in vitro cell culture system, we here report that HBV entry into hepatocytes depends on the interaction with the glycosaminoglycan (GAG) side chains of cell-surface–associated Heparan Sulfate Proteoglycans. Binding to GAGs requires the integrity of the pre-S domain as a part of the large (L-) viral envelope protein. HBV infection was abrogated by incubation of virions with heparin, but not the structurally related GAGs chondroitin Sulfate A, B, and C. Infection was also abolished by suramin, a known inhibitor of duck hepatitis B virus infection or highly Sulfated dextran Sulfate. Polycationic substances such as poly-L-lysine, polybrene, and protamine also prevented infection, however, by addressing cellular components. Enzymatic removal of defined acidic carbohydrate structures from the cell surface using heparinase I/III or the obstruction of GAG synthesis by sodium chlorate inhibited HBV infection of HepaRG cells and, moreover, led to a reduction of HBV cell surface binding sites. The biochemical analysis showed selective binding of L-protein–enriched viral particles (virions or filaments) to heparin. GAG-dependent binding of HBV was improved by polyethylene glycol, a substance that specifically enhances HBV infection. Conclusion: HBV infection requires the initial attachment to the carbohydrate side chains of hepatocyte-associated Heparan Sulfate Proteoglycans as attachment receptors. This interaction initializes the multistep entry process of HBV and cannot be bypassed by alternative routes. (HEPATOLOGY 2007;46:1759–1768.)