[Hepatitis B virus in human pathology. I. Structural and antigenic analysis, hepadnaviridae, epidemiology, patho- and morphogenesis of hepatic lesions].
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Experimental WHV infection of woodchucks: an animal model of hepadnavirus-induced liver cancer.
Woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to HBV in its virus structure, genetic organization and mechanism of replication. Natural infection of woodchucks is associated with chronic liver disease and primary hepatocellular carcinoma (HCC). A concerted effort to develop the woodchuck as an experimental animal model of hepadnavirus-induced disease was initiated in 1980. The experimental studies have established the following: (1) Chronic WHV carriage as an outcome of infection is a function of age of exposure, virus dose and, possibly, virus strain. As in humans, animals infected as newborns develop chronic antigenemia at high rates compared to young adults. (2) WHV causes primary hepatocellular carcinoma (HCC) in woodchucks. Hundred percent of experimentally-induced chronic WHsAg carriers developed HCC within three years; no HCC has occurred in concurrent uninfected control animals born and held in the same laboratory environment. The predictable course of experimental WHV infection leading to liver disease in woodchucks makes this an ideal model in which to study the natural history of hepadnavirus and to develop effective prophylactic and therapeutic strategies.
Animals↗
Hepadnaviruses, their infections and hepatocellular carcinoma.
Ten years ago hepatitis B virus (HBV) was thought to be a unique virus, not included in any known family of viruses. Following the discovery of a number of HBV-like viruses that infect birds and mammals, the existence of a new family known as hepadnaviridae has been confirmed. Hepadnaviruses are small hepatotropic viruses that have a characteristic partially double stranded genome, exhibit a narrow host range and replicate by reverse transcription. The family currently comprises six viruses of which human hepatitis B virus is the prototype member. Other members include woodchuck hepatitis virus (WHV), ground squirrel hepatitis virus (GSHV), tree squirrel hepatitis virus (TSHV). Peking duck hepatitis B virus (DHBV) and heron hepatitis B virus (HHBV). Candidate members of the family include kangaroo hepatitis virus (KHV) and stink snake hepatitis virus (SSHV). In humans, infection with HBV is associated with a wide spectrum of clinical conditions including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Infection with HBV is endemic throughout much of the world and the virus is maintained by the enormous reservoir of over 300 million chronic carriers. For almost 20 years experimental work on hepadnaviruses has been carried out using either natural hosts or cultured cells that were capable to support synthesis of a few viral gene products but unable to execute a complete cycle of virus replication. In this article, we have attempted to summarize the efforts made towards understanding the biology of hepadnaviruses, the nature of their infections and their association with primary liver cancer.
Carcinoma, Hepatocellular↗
Hepadnavirus-induced liver cancer in woodchucks.
Woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to hepatitis B virus (HBV) in its virus structure, genetic organization, and mechanism of replication. As with HBV in man, persistent WHV infection is common in natural woodchuck populations and is associated with chronic hepatitis and hepatocellular carcinoma (HCC). In 1980, a program was initiated to develop the woodchuck as an experimental model of hepadnavirus infection and disease. The experimental studies have established that WHV causes HCC in woodchucks. Chronic WHV carriage as an outcome of experimental infection is a function of animal age at time of exposure, virus dose, and, possibly, virus strain. Almost all (97%) chronic carriers developed histologically confirmed HCC within 3 years; no HCC developed in uninfected animals held concurrently in the same laboratory setting. The model has application to studies of the underlying mechanisms of hepadnavirus-induced hepatocarcinogenesis and to the development of prophylactic and therapeutic strategies of disease control.
Animals↗
Translational inactivation of RNA function: discrimination against a subset of genomic transcripts during HBV nucleocapsid assembly.
Hepatitis B virus (HVB) is the prototype member of the hepadnaviridae, a family of small enveloped DNA viruses that replicate by reverse transcription. Assembly of replication-competent HBV nucleocapsids is based on specific interactions between the core protein, the product(s) of the P gene, and the RNA pregenome, which is marked for encapsidation by containing a sequence near its 5' end that acts in cis as an encapsidation signal. However, HBV produces several additional, almost identical, genomic transcripts that also bear the encapsidation sequence, but that are not encapsidated. The mechanism underlying this selection process has remained mysterious. Here we demonstrate that translating 80S ribosomes (but not scanning 40S ribosomal subunits) advancing into the encapsidation signal prevent its functioning. This finding reveals translational modulation of RNA function as a further regulatory mechanism employed by hepadnaviruses to utilize efficiently the restricted coding capacity of their extremely compact genome.
Amino Acid Sequence↗
The mode of action of interferons in viral infections and their possible role in the control of hepatitis B.
Interferons can alter the course of virus infections by inhibiting virus replication at the intracellular level and by modifying the aspecific and specific immune response to viral antigens in body fluids and on cellular surfaces. Treatment of isolated cells with interferon renders them resistant to infections by viruses belonging to virtually any family. Knowledge of the mechanism of this effect is derived from studies employing both DNA (especially vaccinia virus and SV40) and RNA-viruses (especially picorna-, toga-, rhabdo-, reo- and retroviruses). Interferon induces multiple alterations in the level and state of intracellular regulatory molecules, leading to inhibition of virus replication at several possible steps. In the case of certain DNA viruses, transcription of viral DNA seems to be inhibited. In the case of RNA viruses the target for interferon action is mainly translation. The retroviridae constitute a special case and, in view of their analogy with the hepadnaviridae, are of particular relevance to the possible effects of interferon on the replication of HBV. Interferon inhibits one or more initial stages of primary infection of cells by transforming or nontransforming retroviruses, thereby preventing or delaying the synthesis and/or integration of viral DNA. In cells that already contain an integrated and fully expressed retrovirus genome, interferon treatment results in a reduced release of viral particles as well as a downward shift of the ratios between the numbers of infectious vs noninfectious particles. Immuno-modulatory properties of interferon which might alter the course of HBV-infection include: potentiation of cytotoxic activity of lymphocytes and macrophages; direct anti-inflammatory effects; enhancement or depression in antibody formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The encapsidation signal on the hepatitis B virus RNA pregenome forms a stem-loop structure that is critical for its function.
Hepatitis B virus (HBV) is the type member of the hepadnaviridae, small enveloped DNA viruses that replicate through reverse transcription of an RNA intermediate, the pregenome. This reaction occurs usually inside the viral nucleocapsid, the assembly of which requires specific interactions between multiple copies of the core protein, the viral replication enzyme (P protein) and the RNA pregenome which also serves as mRNA for both proteins. Deletion studies have established that specific packaging of the RNA is mediated by a short cis-acting sequence, the encapsidation signal epsilon. Using nuclease sensitivity experiments we provide experimental evidence that part of this sequence can adopt a stem-loop structure that is interrupted by a bulge and a single unpaired U residue. The structural consequences of deletions of the unpaired regions and changes in their primary sequences were investigated in vitro, and their influence on the function of the epsilon-signal was tested in animal cells by monitoring encapsidation of RNAs carrying the mutant epsilon-sequences in front of a 2.7 kb foreign RNA fragment, or within the context of a complete HBV genome. The data indicate that the entire stem-loop structure containing the bulge and the loop is critical for encapsidation competence. While gross alterations in the primary sequences of the unpaired regions interfere with encapsidation, data obtained with additional mutants suggest that the bulge region is more tolerant to sequence changes than the loop.
Base Sequence↗
Hepatitis B virus replication--an update.
Hepatitis B virus (HBV), the causative agent of type B hepatitis in humans, is the prototypic member of the hepadnaviridae, a family of small enveloped DNA-containing viruses with pronounced host and tissue specificity. This property has greatly hampered progress in understanding the initial events of infection, i.e. attachment, penetration and uncoating. After the discovery, originally made with the duck hepatitis B virus (DHBV), that hepadnaviruses replicate by reverse transcription, DNA transfection of cloned wild-type and mutant HBV genomes into cell lines supporting virion formation has revealed the molecular mechanisms of the late steps of the infectious cycle in some detail. During the last few years, such studies have emphasized the differences between hepadnaviral and retroviral replication. Very recent research, however, indicates that the border separating the two viral families may not be as strict as previously thought. In this article, we will briefly summarize the pertinent differences, and will then focus on the new data, with particular emphasis on the initiation of reverse transcription.
Gene Products, pol↗
Treatment of woodchuck hepatitis virus infection in vivo with 2', -3'-dideoxycytidine (ddC) and 2',-3'-dideoxycytidine monophosphate coupled to lactosaminated human serum albumin (L-HSA ddCMP).
Dideoxycytidine (ddC) is a nucleoside analogue active against human immunodeficiency virus and with in vitro activity against human hepatitis B virus. We investigated the ability of ddC to inhibit one of the Hepadnaviridae, the woodchuck hepatitis virus and compared the results with the effect obtained by a conjugate of lactosaminated human serum albumin 2',-3'-dideoxycytidine monophosphate (L-HSA ddCMP). This compound specifically enters the hepatocyte via the asialoglycoprotein receptor. We treated five chronic woodchuck hepatitis virus carriers with intravenous injections of 0.5 mg/kg body weight of ddC for 5 consecutive days, and under the same protocol five woodchucks with 10.4 mg/ kg L-HSA ddCMP, a dose equivalent to 0.25 mg/kg of free ddC. A reduction of serum woodchuck hepatitis virus DNA (5-125 fold) was observed during therapy in three out of five animals receiving ddC and in two of the five animals treated with L-HSA ddCMP. In responding woodchucks, virus DNA levels rebounded immediately after stopping therapy. No signs of toxicity were observed during or after the course of therapy. These preliminary results of short-term treatment indicate that ddC has anti-viral activity against woodchuck hepatitis virus. When the dose was reduced by 50%, L-HSA ddCMP showed anti-viral activity to an even lesser degree.
Animals↗
Methodological approaches to disinfection of human hepatitis B virus.
Three commercial disinfectants (two quaternary formulations and one phenolic) were tested against human hepatitis B virus (HHBV). The treated virus was assayed for infectivity by the chimpanzee assay and for morphological alteration by the Morphological Alteration and Disintegration Test. The same agents were tested against duck hepatitis B virus in a duck hepatocyte infectivity assay. It is apparent that human and duck hepatitis viruses were relatively susceptible to disinfection, becoming noninfectious after < or = 10 min of contact with the disinfectant. The Morphological Alteration and Disintegration Test accurately predicted activity in the two infectivity tests. The anti-human hepatitis B virus effect of the low-level quaternary ammonium germicides is a novel finding and suggest that members of the family Hepadnaviridae are relatively susceptible to chemical agents.
Animals↗
Long PCR and its application to hepatitis viruses: amplification of hepatitis A, hepatitis B, and hepatitis C virus genomes.
In this study we amplified virtually the entire genomes of hepatitis A virus (a member of the Picornaviridae family), hepatitis B virus (a member of the Hepadnaviridae family), and hepatitis C virus (a member of the Flaviviridae family) by using the recently described technique of long PCR. In order to do this, we first demonstrated, using the lambda phage, that long PCR can be made highly sensitive and the sensitivity can be further enhanced by nested long PCR. We also showed, using tobacco mosaic virus as a model, that a reverse transcriptase reaction can be linked to a long PCR, enabling the nearly full-length amplification of the genomes of RNA viruses. We then applied these techniques to serial dilutions of titrated stocks of well-characterized strains of hepatitis A, B, and C viruses. We amplified the nearly full-length sequence of each of these viruses from a small number of viral genomes, demonstrating the sensitivity of the process.
Bacteriophage lambda↗
An intramolecular disulfide bridge between Cys-7 and Cys61 determines the structure of the secretory core gene product (e antigen) of hepatitis B virus.
Hepatitis B virus, the prototypic member of the Hepadnaviridae, is a small enveloped DNA virus that replicates via reverse transcription. Efficient usage of its compact 3.2-kb genome is exemplified by the pre-C/C gene from which two proteins with largely overlapping primary sequences but distinctly different properties are synthesized: the self-assembling core protein p21c (hepatitis B core antigen [HbcAg]) and the secretory, nonparticulate protein p17e (hepatitis B e antigen [HbeAg]). Mature p17e carries a 10-amino-acid N-terminal extension with a Cys residue (Cys-7). Using transient transfection of a human liver cell line with constructs expressing wild-type p17 or a series of Cys mutants of p17, we show that Cys-7 forms an intramolecular S-S bond to Cys61, which in assembly-competent core proteins is available for intermolecular disulfide bonds between two neighboring subunits. Removal of the Cys-7/Cys61 bond by mutating either residue has differential effects: in the absence of Cys-7, secretion is relatively efficient and independent of Cys61; however, the molecules are exported as homodimers exhibiting both HBe and HBc antigenicity. In the absence of Cys61, the nonpaired Cys-7 interferes with secretion efficiency. The amino acid sequence flanking Cys-7 also contributes to the formation of the proper intramolecular S-S bond. These results suggest that the Cys-7/Cys61 bond imposes on p17e a conformation that is critical for its secretion and distinct biophysical and antigenic properties. This mechanism adds selective disulfide formation to the repertoire of hepatitis B virus for efficient use of its tiny genome.
Amino Acid Sequence↗
Phenotypic mixing of rodent but not avian hepadnavirus surface proteins into human hepatitis B virus particles.
The virus family Hepadnaviridae comprises two genera: orthohepadnaviruses isolated from humans (hepatitis B virus [HBV]) and rodents (e.g., woodchuck hepatitis virus [WHV]) and avihepadnaviruses isolated from birds (e.g., duck hepatitis B virus [DHBV]). They carry in their envelopes two (DHBV) or three (HBV and WHV) coterminal proteins referred to as small (S), middle (M), or large (L) surface protein. These proteins are also secreted from infected cells as subviral particles consisting of surface protein and lipid (e.g., 20-nm hepatitis B surface antigen for HBV). To investigate the assembly of these proteins, we asked whether surface proteins from different hepadnaviruses are able to mix phenotypically with each other. By coexpression and coimmunoprecipitation with species-specific antibodies, we could show the formation of mixed subviral particles and disulfide-linked heterodimers between the WHV S and HBV M proteins whereas the DHBV and HBV surface proteins did not coassemble. Complementation of HBV genomes defective in expressing the S or L protein and therefore incompetent to form virions was possible with the closely related WHV S protein or a WHV pre-S-HBV S chimera, respectively, but not with the less related DHBV S or L protein or with a DHBV L-HBV S chimera. The results suggest that the assembly of HBV subviral particles and virion envelopes requires relatively precise molecular interactions of their surface proteins, which are not conserved between the two hepadnavirus genera. This contrasts with the ability of, e.g., rhabdoviruses or retroviruses, to incorporate envelope proteins even from unrelated viruses.
Base Sequence↗
Taxonomic classification of human hepatitis B virus.
Sufficient data have accumulated to permit the ICTV Study Group on the Nomenclature of Hepatitis Viruses to recognize human hepatitis B virus as a member of a unique group of viruses and to classify it, together with a number of related animal viruses, into a new family called the Hepadnaviridae. Over the past decade, the International Committee on Taxonomy of Viruses (ICTV) has been active in the development of a classification system for viruses. The majority of viruses infecting vertebrate hosts have been classified into families and genera on the recommendations of the Vertebrate Virus Subcommittee (VVSC). In June 1980, the VVSC authorized the formation of an ad hoc Study Group on the Nomenclature of Hepatitis Viruses under the Chairmanship of Dr. Ian D. Gust. This paper represents the first report of the Study Group on the Taxonomic Classification of Human Hepatitis B Virus.
Animals↗
Animal models of hepatocellular carcinoma: hepadnavirus-induced liver cancer in woodchucks.
Woodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to hepatitis-B virus (HBV) in its virus structure, genetic organization, and mechanism of replication. As with HBV in man, persistent WHV infection is common in natural woodchuck populations and is associated with chronic hepatitis and hepatocellular carcinoma (HCC). Experimental studies have established that WHV causes HCC in woodchucks. Chronic WHV carriage as an outcome of experimental infection is a function of animal age at time of exposure, virus dose, and, possibly, virus strain. Almost all (97%) chronic carriers developed histologically confirmed HCC within 3 years while no HCC developed in uninfected animals held concurrently in the same laboratory setting. The model has application in the study of underlying mechanisms of hepadnavirus-induced hepatocarcinogenesis and to the development of prophylactic and therapeutic strategies of disease control.
Animals↗
[Structure of hepatitis B virus and its related serological markers].
Hepatitis B virus (HBV) is a small DNA virus belonging to hepadnaviridae. Genomic DNA of HBV has four open reading frames representing the S gene with pre-S1 and pre-S2 regions for envelope protein, the C gene coding for a nucleocapsid protein, the P gene for the putative DNA polymerase, and the X gene encoding a protein with transcriptional transactivating function. The C gene is preceded in phase by the precore region. Recently, this region has been attracting attention because of its role in the synthesis and secretion of HBe Ag. It has been postulated that HBV mutants with precore region defects prevail in persistently infected hosts along with seroconversion to anti-HBe. Recent advances in molecular biology have enabled us to detect minute amounts of HBV DNA by means of polymerase chain reaction (PCR) and to analyze gene function in detail. The advanced techniques and conventional serological assay systems will help in clarifying the pathogenesis of acute and chronic hepatitis B, in preventing and eradicating HBV infection.
Amino Acid Sequence↗
Detection of an RNase H activity associated with hepadnaviruses.
Replication of the hepadnavirus DNA genome is accomplished via reverse transcription of an intermediate, pregenomic RNA molecule. This process is likely to be carried out by a virally encoded, multifunctional polymerase which possesses DNA- and RNA-dependent DNA polymerase and RNase H activities. However, the nature of the product(s) of the polymerase gene predicted to mediate these functions is unclear. Biochemical studies of the polymerase protein(s) have been limited by its apparent low abundance in virus particles and, until recently, the inability to express active polymerase protein(s) heterologously. We have used activity gel assays to detect DNA- and RNA-dependent DNA polymerase activities associated with highly purified duck hepatitis B virus (DHBV) core particles (S. M. Oberhaus and J. E. Newbold, J. Virol. 67:6558-6566, 1993). Now we report that the same approach identifies a 35-kDa RNase H activity in association with highly purified DHBV core particles and crude preparations of virions from DHBV-infected ducks and woodchuck hepatitis virus-infected woodchucks. This is the first report of the detection of an hepadnavirus-associated RNase H activity. Its apparent size is smaller than any of the DNA polymerase activities that we detected previously and significantly smaller than the full-length protein predicted from the polymerase open reading frame (p85 for DHBV). These data suggest that the viral polymerase and RNase H activities are separable and that these enzymes may coordinate their activities in vivo by forming a complex.
Animals↗
Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma.
Chronic hepadnavirus infection is associated with hepatocellular carcinoma (HCC) in natural hosts such as humans, woodchucks, and Beechey ground squirrels. Several possible oncogenic mechanisms have been identified, including a potential role of the hepadnavirus x (hbx) gene, which transactivates transcription regulated by certain cis-acting sequences, e.g. regulatory sequences of the hepatitis B virus (HBV) and heterologous regulatory sequences of other viruses and cellular genes. The oncogenic potential of hbx is suggested by the observation of HCCs in hbx transgenic mice, the oncogenic transformation of cells expressing hbx in culture, and the transactivation of oncogenes c-myc and c-jun by hbx. Cis-activation of cellular oncogenes N-myc and c-myc by viral promoter insertion has been a common finding in woodchuck hepatitis virus (WHV)-associated HCCs of woodchucks. No such cis-activation of any cellular gene has been shown in virus-associated HCCs of ground squirrels or humans. Amplification and overexpression of the c-myc gene has been a common finding in HCCs of ground squirrels, and is rare in woodchuck or human HCCs. Point mutations in the p53 gene and allelic deletion of p53 have been common findings in human HCCs, but have not been found in HCCs in woodchucks and have been found rarely in ground squirrels. How each of these genetic changes in the different hosts contributes to HCC remains to be determined, but apparently different changes in different HCCs of hepadnavirus-infected hosts suggest that several separate genetic events may contribute to the development of HCC. These events may differ in each host, and some may not result from a direct virus-specific mechanism. Chronic hepadnavirus infection is often associated with chronic necroinflammatory liver disease and cirrhosis, a pathologic process common to several other risk factors for HCC. This suggests that this pathologic process (necroinflammatory disease) may be hepatocarcinogenic regardless of the inciting agent. Thus hepadnavirus infection may play an important role in the development of HCC by causing chronic hepatitis and HCC with the same mechanisms by which other risk factors for HCC cause chronic necroinflammatory liver disease and HCC.
Animals↗