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.

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Available from: Corinna M. Bremer, Sep 09, 2014
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    • "c o m / l o c a t e / b i o c h e m p h a r m important emerging viruses in tropical and subtropical countries with 2.5 billion people at risk to get infected and every year more than 50 million clinical cases of DENV infections [9]. Further, it was shown that several viruses such as HSV-1, hepatitis B virus (HBV), HIV-1, DENV, vaccinia virus (VV) and adenovirus (ADV) bind to glycosaminoglycans (GAGs) for entering and infecting the host cell10111213141516171819. GAGs are linear polysaccharides consisting of repeating disaccharide subunits which can be divided into six classes: heparin, heparan sulfate (HS), chondroitin sulfate, dermatan sulfate, keratan sulfate and hyaluronic acid [20] . "
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    • "The exposed part of the " a " determinant comprises three loops (mini-loop aa 121-124 (Qiu et al., 1996), the first-loop aa 124-137 (Dreesman et al., 1982) and the second loop aa 139-147 (Bhatnagar et al., 1982; Brown et al., 1984) held together by disulfide bonds. The HBV surface proteins bear cellular receptor-binding sites located within the aminoterminal preS1 domain of the LHBs interacting with hepatic bile acid transporter, NTCP (Yan et al., 2012) and the HBsAg " a " determinant interacting with heparin sulfate proteoglycans (Leistner et al., 2008; Sureau and Salisse, 2013). The activity of the receptor-binding site within the " a " determinant depends on cysteine residues that are essential for its conformation (Mangold et al., 1995). "
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