Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) are primate hepadnaviruses that display restricted tissue and host tropisms. Hepatitis D virus (HDV) particles pseudotyped with HBV and WMHBV envelopes (HBV-HDV and WM-HDV) preferentially infect human and spider monkey hepatocytes, respectively, thereby confirming host range bias in vitro. The analysis of chimeric HBV and WMHBV large (L) envelope proteins suggests that the pre-S1 domain may comprise two regions that affect infectivity: one within the amino-terminal 40 amino acids of pre-S1 and one downstream of this region. In the present study, we further characterized the role of the amino terminus of pre-S1 in infectivity by examining the ability of synthetic peptides to competitively block HDV infection of primary human and spider monkey hepatocytes. A synthetic peptide representing the first 45 residues of the pre-S1 domain of the HBV L protein blocked infectivity of HBV-HDV and WM-HDV, with a requirement for myristylation of the amino terminal residue. Competition studies with truncated peptides suggested that pre-S1 residues 5 to 20 represent the minimal domain for inhibition of HDV infection and, thus, presumably represent the residues involved in virus-host receptor interaction. Recombinant pre-S1 proteins expressed in insect cells blocked infection with HBV-HDV and WM-HDV at a concentration of 1 nanomolar. The ability of short pre-S1 peptides to efficiently inhibit HDV infection suggests that they represent suitable ligands for identification of the HBV receptor and that a pre-S1 mimetic may represent a rational therapy for the treatment of HBV infection.The hepatitis B virus (HBV) genome is a relaxed-circular, partially duplex DNA with a covalently attached polymerase that displays reverse transcriptase activities (40,41). The viral glycoproteins contained in the HBV envelope are encoded by a single open reading frame (ORF) and are translated from different in-frame start codons to generate the small (S), middle (M), and large (L) proteins. All three proteins contain the surface domain (S), while the M protein has a 55-amino-acid (aa) extension designated the pre-S2 domain and the L protein contains an additional 108-aa pre-S1 domain. The L protein is modified at the amino-terminal glycine of the pre-S1 domain with a myristate (37), which is required for infectivity (4, 10, 32). The pre-S1 domain of the L glycoprotein has long been implicated in receptor binding and host range (5,29,43), yet, almost 40 years after the discovery of HBV, no receptor has been positively identified. Receptor candidates that are pre-S1-binding proteins have included the interleukin-6 receptor (35) and an immunoglobulin A-binding protein on hepatocytes (38). More recently, two groups have identified additional pre-S1-binding proteins. Ryu et al. identified an 80-kDa protein using a glutathione S-transferase-pre-S1 fusion protein (39), while De Falco et al. identified a 44-kDa protein (6) by using the pre-S1 peptide originally shown to bind liver cells by Ne...
Hepatitis B virus (HBV) and woolly monkey hepatitis B virus (WMHBV) have natural host ranges that are limited to closely related species. The barrier for infection of primates seems to be at the adsorption and/or entry steps of the viral replication cycle, since a human hepatoma cell line is permissive for HBV and WMHBV replication following transfection of cloned DNA. We hypothesized that the HBV and WMHBV envelope proteins contain the principal viral determinants of host range. As previously shown by using the hepatitis D virus (HDV) system, recombinant HBV-HDV particles were infectious in chimpanzee as well as human hepatocytes. We extended the HDV system to include HDV particles pseudotyped with the WMHBV envelope. In agreement with the natural host ranges of HBV and WMHBV, in vitro infections demonstrated that HBV-HDV and WM-HDV particles preferentially infected human and spider monkey cells, respectively. Previous studies have implicated the pre-S1 region of the large (L) envelope protein in receptor binding and host range; therefore, recombinant HDV particles were pseudotyped with the hepadnaviral envelopes containing chimeric L proteins with the first 40 amino acids from the pre-S1 domain exchanged between HBV and WMHBV. Surprisingly, addition of the human amino terminus to the WMHBV L protein increased infectivity on spider monkey hepatocytes but did not increase infectivity for human hepatocytes. Based upon these data, we discuss the possibility that the L protein may be comprised of two domains that affect infectivity and that sequences downstream of residue 40 may influence host range and receptor binding or entry.Many virus-receptor interactions contribute to viral host range and therefore constitute an interspecies barrier, as is the most apparent circumstance for hepatitis B virus (HBV). Hepadnaviruses, like HBV, characteristically display very narrow host ranges that extend only to closely related species. The discovery and characterization of a nonhuman primate hepadnavirus from woolly monkeys confirmed the restrictions on the transmissibility of the virus between species, as chimpanzees were not susceptible to an efficient infection with woolly monkey hepatitis B virus (WMHBV) (18). However, analyses of the host range of WMHBV indicated that the host range extends to the close relative of the woolly monkey, the black-handed spider monkey; both primates are within the Atelidae family and the Atelinae subfamily. Transfection of the cloned genomes for both HBV and WMHBV into the human liver cell line Huh7 demonstrated assembly of infectious particles following unimpeded replication of both viruses (17), suggesting that the barrier for interspecies transmission is at the initial steps of infection, which include virus adsorption and uptake.The viral glycoproteins contained in the HBV envelope are encoded by a single open reading frame and are translated from different in-frame start codons to a common stop codon to generate the small (S), middle (M), and large (L) proteins. All three proteins conta...
Members of the Hepadnaviridae family have been isolated from birds, rodents, and primates. A new hepadnavirus isolated from the woolly monkey, a New World primate, is phylogenetically distinct from other primate isolates. An animal model has been established for woolly monkey hepatitis B virus (WMHBV) by using spider monkeys, since woolly monkeys are endangered. In this study, a greater-than-genome length construct was prepared without amplification by using covalently closed circular DNA extracted from the liver of an infected woolly monkey. Transfection of the human liver cell line Huh7 with WMHBV DNA resulted in the production of viral transcripts, DNA replicative intermediates, and secreted virions at levels similar to those obtained with an infectious human HBV clone, demonstrating that the host range restriction of WMHBV is not at the level of genome replication. WMHBV particles from the medium of transfected cultures initiated an infection in a spider monkey similar to that obtained with virions derived from woolly monkey serum. In an attempt to adapt the virus for higher levels of replication in spider monkeys, immunosuppressed and newborn animals were inoculated. Neither procedure produced persistent infections, and the level of viral replication remained several logs lower than that observed in persistently infected woolly monkeys. These data demonstrate the production of an infectious clone for WMHBV and extend the characterization of the spider monkey animal model. Hepatitis B virus (HBV) infections represent a worldwide health problem. Although acute HBV infection in adults isnormally self-limiting, serious liver disease, including fulminant hepatitis, often develops. In addition, approximately 5 to 10% of the individuals infected as adults and 95% of those infected at birth become chronically infected. Persistently infected individuals are at risk for cirrhosis, end stage liver disease, and hepatocellular carcinoma (2). Most of our understanding of the pathogenesis and replication of HBV has been obtained by the use of related hepadnaviruses and their animal models, including duck HBV (12), woodchuck hepatitis virus (17), ground squirrel hepatitis virus (11), arctic ground squirrel hepatitis virus (20), heron hepatitis virus (16), and stork hepatitis virus (14). Infection of chimpanzees with human HBV is the only primate model for the analysis of HBV infections. Recently, a number of hepadnaviruses have been isolated from nonhuman primates. Most of the nonhuman primate isolates were from apes and clustered phylogenetically with human HBV isolates. Viruses have been isolated from gibbons (8, 13), chimpanzees (4,5,10,19,21), and orangutans (22). The origins of these viruses remain controversial. Although cross-species transmission from humans cannot be ruled out, chimpanzees from different geographical regions appear to be infected with distinct isolates (4), lending support to the concept that these viruses may have evolved with their hosts. However, the hepadnavirus isolated from woolly monkeys, wo...
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