[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↗
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↗
[Experimental models for the study of hepadnaviruses and antiviral strategies].
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Animals↗
Characterization of the incorporation of woodchuck hepatitis virus surface antigen into hepatocyte plasma membrane in woodchuck hepatitis and in the virus-induced hepatocellular carcinoma.
Interaction between woodchuck hepatitis virus surface antigen and proteins of hepatocyte plasma membranes were examined in the course of woodchuck hepatitis virus infection. Membranes purified from animals with histologically confirmed acute hepatitis, active or persistent chronic hepatitis and the virus-related hepatocellular carcinoma were evaluated for the virus surface antigen contents, treated with agents eluting plasma membrane-bound antigen to test the extent of the antigen-membrane associations and incubated with purified, particulate woodchuck hepatitis virus surface antigen to determine membrane potential for the antigen adsorption. Hepatocyte plasma membranes originating from woodchucks chronically infected with the virus showed the highest quantities of the incorporated virus surface antigen among membranes studied, the behavior of bound antigen as an integral and a peripheral membrane protein and the resistance to bind an exogenous antigen. Similar properties were expressed by plasma membranes prepared from hepatocytes of nontumor parenchyma displaying chronic active hepatitis of a woodchuck hepatitis virus carrier with hepatoma. Furthermore, plasma membranes originating from animals with active or persistent chronic hepatitis demonstrated identical properties, implicating that histologic activity of the chronic liver inflammatory process is not dependent on the quantity of the virus surface antigen insertion into the membrane. In contrast, hepatocyte plasma membranes from animals with acute hepatitis showed significantly lower antigen quantities, presence of the antigen specificity exclusively behaving as an integral membrane protein and noticeable ability to bind an exogenous surface antigen of the virus. Comparable, but not identical, features were observed for hepatocyte membranes purified from nodules of hepatocellular carcinoma, suggesting that neoplastic transformation of infected hepatocytes is associated with loss of the membrane-bound antigen and with simultaneous, partial recovery of the membrane potential for the antigen binding. Comparative analysis of the properties on the woodchuck hepatitis virus surface antigen incorporation into hepatocyte plasma membranes in studied cases indicated that sustained infection with woodchuck hepatitis virus leads to an increase in the quantity of the membrane-incorporated antigen and to the appearance of the virus surface antigen specificity behaving as a peripheral membrane protein. In conclusion, this study demonstrated that the extent and the character of the antigen interaction with hepatocyte plasma membranes undergoes significant variations in the natural course of hepadna viral infect
Animals↗
Alpha-fetoprotein in the woodchuck model of hepadnavirus infection and disease: immunochemical analysis of woodchuck alpha-fetoprotein and measurement in serum by quantitative monoclonal radioimmunoassay.
Woodchuck hepatitis virus infection of the eastern woodchuck represents a useful model for the study of hepatitis B virus infection and disease in humans, including hepatocellular carcinoma. In man, hepatocellular carcinoma is frequently detected and monitored using assays for serum alpha-fetoprotein. To study the relationship between alpha-fetoprotein and woodchuck hepatitis virus-induced hepatocellular carcinoma in the woodchuck model, we produced a monoclonal antibody to woodchuck alpha-fetoprotein and used biophysical and immunochemical methods to demonstrate its specificity and affinity (7 x 10(8) L/mol) for woodchuck alpha-fetoprotein. A competition radioimmunoassay was then developed and standardized for measuring serum alpha-fetoprotein concentrations. In the radioimmunoassay system, woodchuck alpha-fetoprotein was detected between 20 ng/ml (20% to 25% inhibition) and 8,500 ng/ml (97% to 98% inhibition). Elevated serum alpha-fetoprotein concentrations (450 to 452,000 ng/ml) were measured in 21 of 23 woodchucks in the advanced stages of woodchuck hepatitis virus-induced hepatocellular carcinoma. Serum alpha-fetoprotein was elevated above normal (greater than or equal to 450 ng/ml) as early as 3 to 11 mo before terminal hepatocellular carcinoma in 11 of 16 of the woodchuck hepatitis virus-carrier woodchucks. In a pilot study, serum alpha-fetoprotein became markedly elevated above normal in woodchuck hepatitis virus-carrier woodchucks that developed hepatocellular carcinoma but not in serologically recovered or uninfected woodchucks (i.e., without hepatocellular carcinoma). Thus, alpha-fetoprotein may provide a useful noninvasive marker in the woodchuck model for detecting and monitoring woodchuck hepatitis virus-induced hepatocellular carcinoma from earlier stages.
Animals↗
Significance of extrahepatic replication of hepatitis B virus.
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Animals↗
Adenine arabinoside monophosphate and acyclovir monophosphate coupled to lactosaminated albumin reduce woodchuck hepatitis virus viremia at doses lower than do the unconjugated drugs.
The woodchuck was selected to study the efficacy of liver-targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver-targeting molecule lactosaminated human serum albumin. Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively. These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin.
Acyclovir↗
Hepadnaviruses in cirrhotic liver and hepatocellular carcinoma.
Hepadnaviruses share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects, including an association with hepatocellular carcinoma (HCC). Epidemiologic evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80-90%) but not all hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC associated with HBV infections, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10-15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism. It is possible, however, that oncogenic mutations could arise via other mutagenic mechanism that may operate in chronic hepatitis B and/or cirrhosis and which do not involve persisting viral integrations. For example, liver regeneration, which is a feature of the cirrhosis associated with chronic HBV infection (and sometimes with chronic hepatitis B) involves proliferation of many cells with HBV integrations, and such integrations have been shown to be unstable and may lead to mutations through post-integration rearrangements of cellular sequences at sites of viral integrations. Viral sequences appear to be lost or deleted at some such sites of rearranged cell DNA. Chronic HBV infection shares pathologic features of liver cell injury and reactive inflammation, liver regeneration, and in man sometimes cirrhosis with other important risk factors for HCC including chronic alcoholic liver disease, chronic non-A, non-B hepatitis, hemochromatosis, and crypogenic cirrhosis, suggesting that this common pathologic process may be carcinogenic by a mechanism that does not depend specifically on the factor which initiates liver cell injury. The pathogenetic role of chronic hepadnavirus infection in such a process would be in causing liver cell injury with reactive inflammation and hepatocyte proliferation (regeneration).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗