Pre-S1 Antigen-Dependent Infection of
            <i>Tupaia</i>
            Hepatocyte Cultures with Human Hepatitis B Virus

Glebe, Dieter; Aliakbari, Mehriar; Krass, Peter; Knoop, Eva V.; Valerius, Klaus P.; Gerlich, Wolfram H.

doi:10.1128/jvi.77.17.9511-9521.2003

Cited by 168 publications

(121 citation statements)

References 53 publications

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“…It was first reported in the 1980s that the northern tree shrew (T. belangeri) , a small animal close to primates, can be infected by HBV [33,34]. Subsequent studies confirmed the finding and further demonstrated that primary Tupaia hepatocytes can be infected by the virus [35,36]. Intriguingly, conventional model animals (e.g.…”

Section: Ntcp Critically Determines Species Specificity Of Hbv and Hdsupporting

confidence: 51%

Sodium Taurocholate Cotransporting Polypeptide Acts as a Receptor for Hepatitis B and D Virus

Yan

Li²

2015

Dig Dis

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Infection of hepatitis B virus (HBV) remains a major public health problem worldwide. Understanding the viral infection and developing antivirals against HBV have been hampered by the lack of convenient culture systems and animal models for the infection. Sodium taurocholate cotransporting polypeptide (NTCP), a key bile acid transporter expressed in liver, was recently identified as a critical receptor for viral entry of HBV and its satellite virus hepatitis D virus (HDV). This finding enabled a reliable cell culture system for the viruses. Detailed studies have shown that NTCP is the major determinant for the species specificity of HBV and HDV at entry level. NTCP is responsible for most sodium-dependent bile salt uptake in liver. The molecular determinant critical for HBV/HDV infection overlaps with that for bile acids transporting on NTCP. We evaluated bile acids as potential antivirals for HBV and HDV infection, and developed bile acid derivatives that effectively block taurocholate transporting as well as viral infections. The discovery that NTCP acts as a receptor for HBV has opens a new door for future studies towards the ultimate goal of curative treatment of HBV infection.

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Section: Ntcp Critically Determines Species Specificity Of Hbv and Hdsupporting

confidence: 51%

Sodium Taurocholate Cotransporting Polypeptide Acts as a Receptor for Hepatitis B and D Virus

Yan

Li²

2015

Dig Dis

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“…Cultures of primary duck hepatocytes (PDHs) can be readily established and efficiently infected (3,4) and therefore provide a suitable tool for analyzing the early steps of hepadnaviral infection on the molecular level. As for HBV (5)(6)(7), it is known that DHBV infection is initiated by attachment of the virus particle to the hepatocyte surface via the pre-S domain of the viral surface protein L (8,9). In DHBV there are two surface proteins embedded in the lipid envelope: The major S protein, a transmembrane protein that encompasses 167 aa, and the L protein, consisting of the S domain N-terminally extended by the 160-aa pre-S domain.…”

mentioning

confidence: 99%

Identification of a structural motif crucial for infectivity of hepatitis B viruses

Stoeckl

Funk²,

Kopitzki³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Infectious entry of hepatitis B viruses (HBV) has nonconventional facets. Here we analyzed whether a cell-permeable peptide [translocation motif (TLM)] identified within the surface protein of human HBV is a general feature of all hepadnaviruses and plays a role in the viral life cycle. Surface proteins of all hepadnaviruses contain conserved functional TLMs. Genetic inactivation of the duck HBV TLMs does not interfere with viral morphogenesis; however, these mutants are noninfectious. TLM mutant viruses bind to cells and are taken up into the endosomal compartment, but they cannot escape from endosomes. Processing of surface protein by endosomal proteases induces their exposure on the virus surface. This unmasking of TLMs mediates translocation of viral particles across the endosomal membrane into the cytosol, a prerequisite for productive infection. The ability of unmasked TLMs to translocate processed HBV particles across cellular membranes was shown by confocal immunofluorescence microscopy and by infection of nonpermissive cell lines with HBV processed in vitro with endosomal lysate. Based on these data, we propose an infectious entry mechanism unique for hepadnaviruses that involves virus internalization by receptor-mediated endocytosis followed by processing of surface protein in endosomes. This processing activates the function of TLMs that are essential for viral particle translocation through the endosomal membrane into the cytosol and productive infection.cell permeability ͉ envelope protein ͉ virus entry I nfection with human hepatitis B virus (HBV) can cause acute or chronic inflammation of the liver (1, 2). HBV is the prototype member of the hepadnaviridae family, which encompasses members infecting woodchucks, ground squirrels, and avian viruses isolated from, e.g., pekin ducks, gray herons, and storks.Duck HBV (DHBV) is a well characterized model system of hepadnaviral infection (3). Cultures of primary duck hepatocytes (PDHs) can be readily established and efficiently infected (3, 4) and therefore provide a suitable tool for analyzing the early steps of hepadnaviral infection on the molecular level. As for HBV (5-7), it is known that DHBV infection is initiated by attachment of the virus particle to the hepatocyte surface via the pre-S domain of the viral surface protein L (8, 9). In DHBV there are two surface proteins embedded in the lipid envelope: The major S protein, a transmembrane protein that encompasses 167 aa, and the L protein, consisting of the S domain N-terminally extended by the 160-aa pre-S domain. Previous work suggested that DHBV enters the cell by receptor-mediated endocytosis (10-13). The mechanism that allows internalized viral particles to escape from the endocytic pathway remained elusive.Recently, a cell-permeable peptide [translocation motif (TLM)] was identified in the pre-S domain of HBV (14). The TLM is a 12-aa-encompassing domain that forms an amphipathic ␣-helix. It mediates an energy-and receptor-independent transfer of peptides, nucleic acids, and proteins when fus...

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“…Human plasma from chronic hepatitis B patients usually contains a large surplus of subviral particles that could interfere with receptor recognition at the hNTCP. Furthermore, human plasma components have been described to interfere with infection in vitro [35]; therefore, purification of the virions is recommended [35,36]. Ultracentrifugation using various density media (sucrose, percoll) will result in enrichment of virions and separation from the bulk of subviral particles and main plasma components [37,38,39].…”

Section: Phenotypic Assays Based On Infectivity Of Hbv/hdv: Cell Cultmentioning

confidence: 99%

Selected Phenotypic Assays Used to Evaluate Antiviral Resistance and Viral Fitness of Hepatitis B Virus and Its Variants

Glebe¹,

Geipel²

2014

Intervirology

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Currently available antiviral therapies specifically target viral replication by blocking reverse transcription with orally given nucleos(t)ide analogues and are able to specifically suppress viral replication. The unique replication strategy of hepatitis B virus (HBV), however, allows long-term persistence of the viral genome within infected hepatocytes in spite of successful therapy. Thus, antiviral therapy needs to be continued for years. Therapy can result either in the emergence and selection of antiviral-resistant variants or the relapse of viral replication after the termination of antiviral therapy. Resistance is a major problem for 4 of the 5 approved HBV nucleos(t)ide analogues, but it is not the only reason for therapy failure. An accurate phenotypic in vitro assay for resistance allows the identification of a viral variant selected in vivo during antiviral therapy and helps to find therapeutic alternatives. Furthermore, these assays can be used to measure viral fitness and pathogenicity in vitro. With the help of these assays, the prediction of emerging viral variants with drug resistance or increased pathogenic potential can be realized. Phenotypic resistance tests for HBV are not trivial because the virus cannot be readily grown in cell culture. This review focuses on currently available phenotypic assays to evaluate antiviral resistance of HBV and fitness of viral variants in general.

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Pre-S1 Antigen-Dependent Infection of Tupaia Hepatocyte Cultures with Human Hepatitis B Virus

Cited by 168 publications

References 53 publications

Sodium Taurocholate Cotransporting Polypeptide Acts as a Receptor for Hepatitis B and D Virus

Sodium Taurocholate Cotransporting Polypeptide Acts as a Receptor for Hepatitis B and D Virus

Identification of a structural motif crucial for infectivity of hepatitis B viruses

Selected Phenotypic Assays Used to Evaluate Antiviral Resistance and Viral Fitness of Hepatitis B Virus and Its Variants

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