Hepadnaviridae
Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently 18 species in this family, divided among 5 genera. Its best-known member is hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas, and cirrhosis. It is the sole family in the order Blubervirales.
Taxonomy
The following genera are recognized:- Avihepadnavirus
- Orthohepadnavirus
- Herpetohepadnavirus
- Metahepadnavirus
- Parahepadnavirus
History and discovery
Although liver diseases transmissible among human populations were identified early in the history of medicine, the first known hepatitis with a viral etiological agent was Hepatitis A, in the picornaviridae family. Hepatitis B Virus was identified as an infection distinct from Hepatitis A through its contamination of measles, mumps, and yellow fever vaccines in the 1930s and 1940s. These vaccines contained HBV-infected human serum as a stabilizing agent. HBV was identified as a new DNA virus in the 1960s, followed a couple of decades later by the discovery of the flavivirus hepatitis C. HBV was first identified in the lab as the "Australia agent" by Blumberg and colleagues in the blood of an Aboriginal transfusion patient. This work earned Blumberg the 1976 Nobel Prize in Medicine.Genome
Hepadnaviruses have very small genomes of partially double-stranded, partially single stranded circular DNA. The genome consists of two strands, a longer negative-sense strand and a shorter and positive-sense strand of variable length. In the virion these strands are arranged such that the two ends of the long strand meet but are not covalently bonded together. The shorter strand overlaps this divide and is connected to the longer strand on either side of the split through a direct repeat segment that pairs the two strands together. In replication, the viral pdsDNA is converted in the host cell nucleus to covalently-closed-circular DNA by the viral polymerase.As it is a group 7 virus, replication involves an RNA intermediate. Four main open reading frames are encoded and the virus has four known genes which encode seven proteins: the core capsid protein, the viral polymerase, surface antigens—preS1, preS2, and S, the X protein and HBeAg. The X protein is thought to be non-structural. Its function and significance are poorly understood but it is suspected to be associated with host gene expression modulation.
Viral polymerase
Hepadnaviridae encode their own polymerase, rather than co-opting host machinery as some other viruses do. This enzyme is unique among viral polymerases in that it has reverse transcriptase activity to convert RNA into DNA to replicate the genome, RNAse activity, and DNA-dependent-DNA-polymerase activity.Envelope proteins
The hepatitis envelope proteins are composed of subunits made from the viral preS1, preS2, and S genes. The L envelope protein contains all three subunits. The M protein contains only preS2 and S. The S protein contains only S. The genome portions encoding these envelope protein subuntis share both the same frame and the same stop codon, followed directly by the pre-S2 and the S. When a transcript is made from the beginning of the pre-S1 region, all three genes are included in the transcript and the L protein is produced. When the transcript starts after the pro-S1 at the beginning of the pre-S2 the final protein contains the pre-S2 and S subunits only and therefore is an M protein. The smallest envelope protein containing just the S subunit is made most because it is encoded closest to the 3' end and comes from the shortest transcript. These envelope proteins can assemble independently of the viral capsid and genome into non-infectious virus-like particles that give the virus a pleomorphic appearance and promote a strong immune response in hosts.Replication
Hepadnaviruses replicate through an RNA intermediate. The reverse transcriptase becomes covalently linked to a short 3- or 4-nucleotide primer. Most hepadnaviruses will only replicate in specific hosts, and this makes experiments using in vitro methods very difficult.The virus binds to specific receptors on cells and the core particle enters the cell cytoplasm. This is then translocated to the nucleus, where the partially double stranded DNA is 'repaired' by the viral polymerase to form a complete circular dsDNA genome. The genome then undergoes transcription by the host cell RNA polymerase and the pregenomicRNA is sent out of the nucleus. The pgRNA is inserted into an assembled viral capsid containing the viral polymerase. Inside this capsid the genome is converted from RNA to pdsDNA through activity of the polymerase as an RNA-dependent-DNA-polymerase and subsequently as an RNAse to eliminate the pgRNA transcript. These new virions either leave the cell to infect others or are immediately dismantled so the new viral genomes can enter the nucleus and magnify the infection. The virions that leave the cell egress through budding.
| Genus | Host details | Tissue tropism | Entry details | Release details | Replication site | Assembly site | Transmission |
| Avihepadnavirus | Birds | Hepatocytes | Cell receptor endocytosis | Budding | Nucleus | Cytoplasm | Vertical: parental; sex; blood |
| Orthohepadnavirus | Humans; mammals | Hepatocytes | Cell receptor endocytosis | Budding | Nucleus | Cytoplasm | Vertical: parental; sex; blood |
Structure
Viruses in Hepadnaviridae are enveloped, with spherical geometries, and T=4 symmetry. The diameter is around 42 nm. Genomes are circular, around 3.2kb in length. The genome codes for 7 proteins.| Genus | Structure | Symmetry | Capsid | Genomic arrangement | Genomic segmentation |
| Avihepadnavirus | Icosahedral | T=4 | Non-enveloped | Circular | Monopartite |
| Orthohepadnavirus | Icosahedral | T=4 | Non-enveloped | Circular | Monopartite |
Evolution
Based on the presence of viral genomes in bird DNA it appears that the hepadnaviruses evolved >. Birds may be the original hosts of the Hepadnaviridae with mammals becoming infected after a bird.Endogenous hepatitis B virus genomes have been described in crocodilian, snake and turtle genomes. This suggests that these viruses have infected vertebrates for over.
Hepadnaviruses have been described in fish and amphibians also. This suggests that this family has co-evolved with the vertebrates.
Phylogenetic trees suggest that the bird viruses originated from those infecting reptiles. Those affecting mammals appear to be more closely related to those found in fish.
A family of viruses - the Nackednaviridae - has been isolated from fish. This family has a similar genomic organisation to that of the Hepadnaviridae. These two families separated over suggesting an ancient origin for the Hepadnaviridae.