Primary Human Hepatocytes Are Susceptible to Infection by Hepatitis Delta Virus Assembled with Envelope Proteins of Woodchuck Hepatitis Virus

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
Journal of Virology (Impact Factor: 4.44). 09/2008; 82(15):7276-83. DOI: 10.1128/JVI.00576-08
Source: PubMed


Hepatitis B virus (HBV) and hepatitis delta virus (HDV) share the HBV envelope proteins. When woodchucks chronically infected
with woodchuck hepatitis virus (WHV) are superinfected with HDV, they produce HDV with a WHV envelope, wHDV. Several lines
of evidence are provided that wHDV infects not only cultured primary woodchuck hepatocytes (PWH) but also primary human hepatocytes
(PHH). Surprisingly, HBV-enveloped HDV (hHDV) and wHDV infected PHH with comparable efficiencies; however, hHDV did not infect
PWH. The basis for these host range specificities was investigated using as inhibitors peptides bearing species-specific pre-S
(where S is the small envelope protein) sequences. It was found that pre-S1 contributed to the ability of wHDV to infect both
PHH and PWH. In addition, the inability of hHDV to infect PWH was not overcome using a chimeric form of hHDV containing WHV
S protein, again supporting the essential role of pre-S1 in infection of target cells. One interpretation of these data is
that host range specificity of HDV is determined entirely by pre-S1 and that the WHV and HBV pre-S1 proteins recognize different
receptors on PHH.

Download full-text


Available from: Stephan Urban, Mar 10, 2014
  • Source
    • "Recent data, however, raise the question whether HDV is a suitable model system to study HBV entry. While chimeric particles harboring woodchuck envelope proteins are unable to infect PHHs, a recombinant HDV assembled with envelope proteins of WHV infects PHHs, indicating significant differences between the entry process of HDV and HBV [113]. Detailed analysis of the TLM-mutated HBV [112] reveals that due to the partial deletion of either the C-terminal or N-terminal part of the TLM a novel functional TLM was generated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis B virus (HBV) is a major cause of liver disease. HBV primarily infects hepatocytes by a still poorly understood mechanism. After an endocytotic process, the nucleocapsids are released into the cytoplasm and the relaxed circular rcDNA genome is transported towards the nucleus where it is converted into covalently closed circular cccDNA. Replication of the viral genome occurs via an RNA pregenome (pgRNA) that binds to HBV polymerase (P). P initiates pgRNA encapsidation and reverse transcription inside the capsid. Matured, rcDNA containing nucleocapsids can re-deliver the RC-DNA to the nucleus, or be secreted via interaction with the envelope proteins as progeny virions.
    Viruses 09/2009; 1(2):185-209. DOI:10.3390/v1020185 · 3.35 Impact Factor
  • Source
    • "The HBsAg coat is not exclusive, as HDV can coat also within the woodchuck hepatitis virus (WHV) surface antigen and in vivo HDV has been passed from chimpanzees to the rodent [4]. However, in apparent contradiction to the in vivo transmission of primate HDV to woodchucks, woodchuck-HDV was reported to infect cultured primary woodchuck hepatocytes as well as cultures of primary human hepatocytes, but human HDV could not infect woodchuck hepatocytes [22]; the different host-range specificities seems determined by the different recognition of WHV and HBV Pre S1 proteins on human hepatocytes. Conventional RNA viruses undergo replication by a virus encoded RNA-dependent RNA-polymerase which replicates the viral genome; they cannot use cellular RNA-polymerases, as these accept only DNA templates . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The key to the discovery of the Hepatitis D Virus (HDV) was the description in Turin, Italy in the mid-1970s of the delta antigen and antibody in carriers of the hepatitis B surface antigen. The new antigen was first thought to be a marker of the Hepatitis B Virus (HBV) and in view of its intricate true nature, it would have possibly died away as another odd antigenic subtype of HBV, like many that were described in the 1970s. Fortunately, instead, a collaboration started in 1978 between the Turin group, and the National Institute of Health and Georgetown University in the US. With American facilities and expertise this collaboration led just a year later, in 1979, to the unfolding of an unexpected and amazing chapter in virology. Experiments in chimpanzees demonstrated that the delta antigen was not a component of the HBV but of a separate defective virus requiring HBV for its infection; it was named the hepatitis D virus to conform to the nomenclature of hepatitis viruses and classified within the genus Deltavirus. The animal experiments were also seminal in proposing to future clinical interpretation, the paradigm of a pathogenic infection (hepatitis D), that could develop only in HBV-infected patients, was mainly transmitted by superinfection of HDV on chronic HBV carriers and had the ability to strongly inhibit the helper HBV. The discovery of the HDV has driven three directions of further research: (1) The understanding of the replicative and infectious mechanisms of the HDV. (2) The assessment of its epidemiological and medical impact. (3) The search for a therapy for chronic hepatitis D (CHD). This review summarizes the progress achieved in each field of research in the thirty years that have passed since the discovery of HDV.
    Journal of Hepatology 03/2009; 50(5):1043-50. DOI:10.1016/j.jhep.2009.01.004 · 11.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepadnaviruses, including hepatitis B virus (HBV), a highly relevant human pathogen, are small enveloped DNA viruses that replicate via reverse transcription. All hepadnaviruses display a narrow tissue and host tropism. For HBV, this restricts efficient experimental in vivo infection to chimpanzees. While the cellular factors mediating infection are largely unknown, the large viral envelope protein (L) plays a pivotal role for infectivity. Furthermore, certain segments of the PreS domain of L from duck HBV (DHBV) enhanced infectivity for cultured duck hepatocytes of pseudotyped heron HBV (HHBV), a virus unable to infect ducks in vivo. This implied a crucial role for the PreS sequence from amino acid 22 to 90 in the duck tropism of DHBV. Reasoning that reciprocal replacements would reduce infectivity for ducks, we generated spreading-competent chimeric DHBVs with L proteins in which segments 22-90 (Du-He4) or its subsegments 22-37 and 37-90 (Du-He2, Du-He3) are derived from HHBV. Infectivity for duck hepatocytes of Du-He4 and Du-He3, though not Du-He2, was indeed clearly reduced compared to wild-type DHBV. Surprisingly, however, in ducks even Du-He4 caused high-titered, persistent, horizontally and vertically transmissable infections, with kinetics of viral spread similar to those of DHBV when inoculated at doses of 10(8) viral genome equivalents (vge) per animal. Low-dose infections down to 300 vge per duck did not reveal a significant reduction in specific infectivity of the chimera. Hence, sequence alterations in PreS that limited infectivity in vitro did not do so in vivo. These data reveal a much more complex correlation between PreS sequence and host specificity than might have been anticipated; more generally, they question the value of cultured hepatocytes for reliably predicting in vivo infectivity of avian and, by inference, mammalian hepadnaviruses, with potential implications for the risk assessment of vaccine and drug resistant HBV variants.
    PLoS Pathogens 01/2009; 4(12):e1000230. DOI:10.1371/journal.ppat.1000230 · 7.56 Impact Factor
Show more