Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has...Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.展开更多
Hepadnaviruses, including human hepatitis B virus （HBV）, replicate through reverse transcription of an RNA intermediate, the pregenomic RNA （pgRNA）. Despite this kinship to retroviruses, there are fundamental diff...Hepadnaviruses, including human hepatitis B virus （HBV）, replicate through reverse transcription of an RNA intermediate, the pregenomic RNA （pgRNA）. Despite this kinship to retroviruses, there are fundamental differences beyond the fact that hepadnavirions contain DNA instead of RNA. Most peculiar is the initiation of reverse transcription： it occurs by protein-priming, is strictly committed to using an RNA hairpin on the pgRNA, ε, as template, and depends on cellular chaperones; moreover, proper replication can apparently occur only in the specialized environment of intact nucleocapsids. This complexity has hampered an in-depth mechanistic understanding. The recent successful reconstitution in the test tube of active replication initiation complexes from purified components, for duck HBV （DHBV）, now allows for the analysis of the biochemistry of hepadnaviral replication at the molecular level. Here we review the current state of knowledge at all steps of the hepadnaviral genome replication cycle, with emphasis on new insights that turned up by the use of such cellfree systems. At this time, they can, unfortunately, not be complemented by three-dimensional structural information on the involved components. However, at least for the ~ RNA element such information is emerging, raising expectations that combining biophysics with biochemistry and genetics will soon provide a powerful integrated approach for solving the many outstanding questions. The ultimate, though most challenging goal, will be to visualize the hepadnaviral reverse transcriptase in the act of synthesizing DNA, which will also have strong implications for drug development.展开更多
The human hepatitis B virus （HBV） and the duck hepatitis B virus （DHBV） share several fundamental features. Both viruses have a partially double-stranded DNA genome that is replicated via a RNA intermediate and th...The human hepatitis B virus （HBV） and the duck hepatitis B virus （DHBV） share several fundamental features. Both viruses have a partially double-stranded DNA genome that is replicated via a RNA intermediate and the coding open reading frames （ORFs） overlap extensively. In addition, the genomic and structural organization, as well as replication and biological characteristics, are very similar in both viruses. Host of the key features of hepadnaviral infection were first discovered in the DHBV model system and subsequently confirmed for HBV. There are, however, several differences between human HBV and DHBV. This review will focus on the molecular and cellular biology, evolution, and host adaptation of the avian hepatitis B viruses with particular emphasis on DHBV as a model system.展开更多
Hepatitis B virus (HBV), a typical member of the Hepadnaviridae family, is responsible for infections that cause B-type hepatitis which leads to severe public health problems around the world. The small enveloped DNA-...Hepatitis B virus (HBV), a typical member of the Hepadnaviridae family, is responsible for infections that cause B-type hepatitis which leads to severe public health problems around the world. The small enveloped DNA-containing virus replicates via reverse transcription, and this unique process is accomplished by the virally encoded reverse transcriptase (RT). This multi-functional protein plays a vital role in the viral life cycle. Here, we provide a summary of current knowledge regarding the structural characteristics and molecular mechanisms of HBV RT. Improved understanding of these processes is of both theoretical and practical significance for fundamental studies of HBV and drug discovery.展开更多
The nucleocapsid of hepadnaviruses consisits of dimers of the core proteins. However, the mechanism of the core-core subunit interaction is not well understood. The Nterminus of the core protein of woodchuck hepatitis...The nucleocapsid of hepadnaviruses consisits of dimers of the core proteins. However, the mechanism of the core-core subunit interaction is not well understood. The Nterminus of the core protein of woodchuck hepatitis virus(WHV) was found containing four conserved hydrophobic amino acid residues (from residue 101 to 122 ). These residues, referred to the hydrophobic heptad repeat(hhr), distributed as heptad repeats in the primary sequence. Since hydrophobic bounds often play an important role in interaction of proteins, roles of the hhr region in capsid assembly of WHV were investigated using a cell culture system. The codons for these four hydrophobic amino acid residues and other related residues in this region were substituted with codons specifying alanine or proline. Phenotype of each of these mutants was examined at various stages of viral replication in Hub7 cells. It was found that single substitution of the four hydrophobic residues had no detectable effect, but substitution of the same residues in various paired combinations resulted in a complete inhibition of capsid assembly. The capsid assembly was inhibited when amino acid insertion occerred at the first and last two hydrophobic residues or a single amino acid deletion occurred at the first pair of hydrophobic residues. However, random amino acid substitutions in this region did not affect assembly. The results indicated that the hhr region of the core protein was necessory for capsid assembly of woodchuck hepatitis virus.展开更多
基金operating research grants from the Canadian Institutes of Health Research, Canada and the Canada Research Chair Program, and the Canada Foundation for Innovation
文摘Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.
文摘Hepadnaviruses, including human hepatitis B virus （HBV）, replicate through reverse transcription of an RNA intermediate, the pregenomic RNA （pgRNA）. Despite this kinship to retroviruses, there are fundamental differences beyond the fact that hepadnavirions contain DNA instead of RNA. Most peculiar is the initiation of reverse transcription： it occurs by protein-priming, is strictly committed to using an RNA hairpin on the pgRNA, ε, as template, and depends on cellular chaperones; moreover, proper replication can apparently occur only in the specialized environment of intact nucleocapsids. This complexity has hampered an in-depth mechanistic understanding. The recent successful reconstitution in the test tube of active replication initiation complexes from purified components, for duck HBV （DHBV）, now allows for the analysis of the biochemistry of hepadnaviral replication at the molecular level. Here we review the current state of knowledge at all steps of the hepadnaviral genome replication cycle, with emphasis on new insights that turned up by the use of such cellfree systems. At this time, they can, unfortunately, not be complemented by three-dimensional structural information on the involved components. However, at least for the ~ RNA element such information is emerging, raising expectations that combining biophysics with biochemistry and genetics will soon provide a powerful integrated approach for solving the many outstanding questions. The ultimate, though most challenging goal, will be to visualize the hepadnaviral reverse transcriptase in the act of synthesizing DNA, which will also have strong implications for drug development.
基金Supported by the Freie und Hansestadt Hamburg and the Bundesministcrium für Gesundheit und Soziale Sicherung grants from DFG and by the German Competence Network for Viral Hepatitis （Hop-Net）, funded by the German Ministry of Education and Research （BMBF）, Grant No. TFI3. IWe apologize to those authors whose work we could not cite directly due to space limitations. The authors are indebted to Claudia Franke （Heinrich-Pette-Institute, Hamburg, Germany） for providing the picture of core protein phosphorylation.
文摘The human hepatitis B virus （HBV） and the duck hepatitis B virus （DHBV） share several fundamental features. Both viruses have a partially double-stranded DNA genome that is replicated via a RNA intermediate and the coding open reading frames （ORFs） overlap extensively. In addition, the genomic and structural organization, as well as replication and biological characteristics, are very similar in both viruses. Host of the key features of hepadnaviral infection were first discovered in the DHBV model system and subsequently confirmed for HBV. There are, however, several differences between human HBV and DHBV. This review will focus on the molecular and cellular biology, evolution, and host adaptation of the avian hepatitis B viruses with particular emphasis on DHBV as a model system.
基金National Nature Science Foundations of China (30870131)Program of Chinese Academy of Sciences (0802021SA1)
文摘Hepatitis B virus (HBV), a typical member of the Hepadnaviridae family, is responsible for infections that cause B-type hepatitis which leads to severe public health problems around the world. The small enveloped DNA-containing virus replicates via reverse transcription, and this unique process is accomplished by the virally encoded reverse transcriptase (RT). This multi-functional protein plays a vital role in the viral life cycle. Here, we provide a summary of current knowledge regarding the structural characteristics and molecular mechanisms of HBV RT. Improved understanding of these processes is of both theoretical and practical significance for fundamental studies of HBV and drug discovery.
文摘The nucleocapsid of hepadnaviruses consisits of dimers of the core proteins. However, the mechanism of the core-core subunit interaction is not well understood. The Nterminus of the core protein of woodchuck hepatitis virus(WHV) was found containing four conserved hydrophobic amino acid residues (from residue 101 to 122 ). These residues, referred to the hydrophobic heptad repeat(hhr), distributed as heptad repeats in the primary sequence. Since hydrophobic bounds often play an important role in interaction of proteins, roles of the hhr region in capsid assembly of WHV were investigated using a cell culture system. The codons for these four hydrophobic amino acid residues and other related residues in this region were substituted with codons specifying alanine or proline. Phenotype of each of these mutants was examined at various stages of viral replication in Hub7 cells. It was found that single substitution of the four hydrophobic residues had no detectable effect, but substitution of the same residues in various paired combinations resulted in a complete inhibition of capsid assembly. The capsid assembly was inhibited when amino acid insertion occerred at the first and last two hydrophobic residues or a single amino acid deletion occurred at the first pair of hydrophobic residues. However, random amino acid substitutions in this region did not affect assembly. The results indicated that the hhr region of the core protein was necessory for capsid assembly of woodchuck hepatitis virus.
