Role of glycosaminoglycans for binding and infection of hepatitis B virus

Institute of Medical Virology, Justus Liebig University, Frankfurter Str. 107, 35392 Giessen, Germany.
Cellular Microbiology (Impact Factor: 4.92). 02/2008; 10(1):122-33. DOI: 10.1111/j.1462-5822.2007.01023.x
Source: PubMed


Many parts of the life cycle of hepatitis B virus (HBV) infection of hepatocytes have been unravelled, but the attachment and entry process leading to infection is largely unknown. Using primary Tupaia hepatocyte cultures as an in vitro infection system, we determined that HBV uses cell-surface heparan sulfate proteoglycans as low-affinity receptor, because HBV infection was inhibited by heparin (IC50: 5 microg ml(-1)) or other higher-sulfated polymers, but not by lower-sulfated glycosaminoglycans, such as chondroitin sulfate. Pretreatment of primary hepatocytes with heparinase decreased viral binding and inhibited HBV infection completely. Interestingly, after preS1-dependent viral binding at 16 degrees C to the cell surface, subsequent infection could still be inhibited by HBV preS1-lipopeptides, but not by heparin any more, suggesting a shift of the virus to a high-affinity receptor. In summary, we suggest following multistep attachment process: in vivo, HBV is initially trapped within the liver in the space of Dissé by heparan sulfate proteoglycans. Thereafter, HBV binds via its preS1 attachment site and the N-terminal myristic acid to a yet unknown, high-affinity receptor that confers uptake in a yet unknown compartment.

Download full-text


Available from: Corinna M. Bremer, Sep 09, 2014
20 Reads
  • Source
    • "GPC1 is a glycophosphatidylinositol (GPI) linked cell surface protein and member of a large group of heparan sulfate binding proteins that are involved in morphogenesis, adhesion, chemotaxis, and inflammation [Fransson, 2003; Parish, 2006]. Heparan sulfate proteoglycans are key cell surface attachment sites for infectious agents and are thought to play a role in the hepatotropism of hepatitis B virus, hepatitis C virus, and hepatitis D [Barth et al., 2003; Schulze et al., 2007; Leistner et al., 2008; Longarela et al., 2013; Shi et al., 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute liver failure is a severe, but rare, outcome of hepatitis A virus infection. Unusual presentations of prevalent infections have often been attributed to pathogen-specific immune deficits that exhibit Mendelian inheritance. Genome-wide resequencing of unrelated cases has proven to be a powerful approach for identifying highly penetrant risk alleles that underlie such syndromes. Rare mutations likely to affect protein expression or function can be identified from sequence data, and their association with a similarly rare phenotype rests on their existence in multiple affected individuals. A rare or novel sequence variant that is enriched to a significant degree in a genetically diverse cohort suggests a candidate susceptibility allele. Whole genome sequencing of ten individuals from ethnically diverse backgrounds with HAV-associated acute liver failure was performed. A set of rational filtering criteria was used to identify genetic variants that are rare in the population, but enriched in this cohort. Single nucleotide polymorphisms, insertions, and deletions were considered and autosomal dominant, autosomal recessive, and polygenic models were applied. Analysis of the protein-coding exome identified no single gene with putatively deleterious mutations shared by multiple individuals, arguing against a simple Mendelian model of inheritance. A number of rare variants were significantly enriched in this cohort, consistent with a complex and genetically heterogeneous trait. Several of the variants identified in this genome-wide study lie within genes important to hepatic pathophysiology and are candidate susceptibility alleles for hepatitis A virus infection. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 10/2014; 86(10). DOI:10.1002/jmv.24007 · 2.35 Impact Factor
  • Source
    • "The ubiquitous heparan sulfate proteoglycans (HSPGs), which are widely distributed on mammalian cells, have been identified as potential targets for a number of viruses [82-85], such as herpes virus [86], hepatitis C virus [87], dengue virus [88], human immunodeficiency virus type 1 [55], foot and mouth disease virus [55], human papillomavirus [89], and hepatitis B virus [90]. It has been shown that HSPGs acts as primary binding sites, promoting viral docking and facilitating subsequent interaction of viruses with the specific cellular receptors [91]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Hepatitis C virus (HCV) infection represents a worldwide health threat that still needs efficient protective vaccine and/or effective drug. The traditional medicine, such as camel milk, is heavily used by the large sector of HCV patients to control the infection due to the high cost of the available standard therapy. Camel milk contains lactoferrin, which plays an important and multifunctional role in innate immunity and specific host defense against microbial infection. Continuing the analysis of the effectiveness of camel lactoferrin against HCV, the current study aimed to separate and purify the native N- and C-lobes from the proteolytically cleaved camel lactoferrin (cLF) and to compare their in vitro activities against the HCV infection in Huh7.5 cells in order to determine the most active domain. Methods Lactoferrin and its digested N- and C-lobes were purified by Mono S 5/50 GL column and Superdex 200 5/150 column. The purified proteins were assessed through three venues: 1. To inhibit intracellular replication, HCV infected cells were treated with the proteins at different concentrations and time intervals; 2. The proteins were directly incubated with the viral particles (neutralization) and then such neutralized viruses were used to infect cells; 3. The cells were protected with proteins before exposure to the virus. The antiviral potentials of the cLf and its lobes were determined using three techniques: 1. RT-nested PCR, 2. Real-time PCR, and 3. Flow cytometry. Results N- and C-lobes were purified in two consecutive steps; using Mono-S and Superdex 200 columns. The molecular mass of N- and C-lobes was about 40 kDa. cLF and its lobes could prevent HCV entry into Huh 7.5 cells with activity reached 100% through direct interaction with the virus. The inhibition of intracellular viral replication by N-lobe is 2-fold and 3-fold more effective than that of the cLF and C-lobe, respectively. Conclusion Generated native N- and C-lobes from camel lactoferrin demonstrated a range of noticeably different potentials against HCV cellular infectivity. The anti-HCV activities were sorted as N-lobe > cLf > C-lobe.
    BMC Complementary and Alternative Medicine 07/2014; 14(1):219. DOI:10.1186/1472-6882-14-219 · 2.02 Impact Factor
  • Source
    • "This experimental tool of human-origin can be employed for investigations addressing HBV entry (attachment , receptor interaction and viral uptake). By using this newly established in vitro system, the relevance of the initial attachment to the carbohydrate side chains of hepatocyte-associated heparan sulphate proteoglycans (HSPGs) as attachment receptors for HBV infection was reported [Schulze et al., 2007; Leistner et al., 2008]. However, because of the ubiquitous expression of heparan sulfate proteoglycans, this finding does not explain the hepatotropism of HBV. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis B virus (HBV) poses a threat to global public health mainly because of complications of HBV-related chronic liver disease. HBV exhibits a narrow host range, replicating primarily in hepatocytes by a still poorly understood mechanism. For the generation of progeny virions, HBV depends on interactions with specific host factors through its life cycle. Revealing and characterizing these interactions are keys to identifying novel antiviral targets, and to developing specific treatment strategies for HBV patients. In this review, recent insights into the HBV-host interactions, especially on virus entry, intracellular trafficking, genome transcription and replication, budding and release, and even cellular restriction factors were reviewed. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 06/2014; 86(6):925-32. DOI:10.1002/jmv.23916 · 2.35 Impact Factor
Show more