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''Hepadnaviridae'' is a family of
viruses A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...
. 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 ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus '' Orthohepadnavirus'' and a member of the '' Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there b ...
. Diseases associated with this family include:
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
infections, such as hepatitis, hepatocellular carcinomas (chronic infections), and cirrhosis. It is the sole accepted family in the order ''Blubervirales''.


Taxonomy

The following genera are recognized: * ''
Avihepadnavirus ''Avihepadnavirus'' is a genus of viruses, in the family '' Hepadnaviridae''. Birds serve as natural hosts. There are three species in this genus. Diseases associated with this genus include: hepatitis, hepatocellular carcinomas (chronic infe ...
'' * ''
Orthohepadnavirus ''Orthohepadnavirus'' is a genus of viruses, in the family '' Hepadnaviridae''. Humans and other mammals serve as natural hosts. There are 12 species in this genus. Diseases associated with this genus include: hepatitis, hepatocellular carcinoma ...
'' * '' 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 Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including fish, mammals, and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30&nbs ...
family. Hepatitis B Virus (HBV) 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 ''Flavivirus'' is a genus of positive-strand RNA viruses in the family ''Flaviviridae''. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cau ...
hepatitis C. HBV was first identified in the lab as the "Australia agent" by
Blumberg For the town in South Australia previously called Blumberg, see Birdwood, South Australia. Blumberg is a municipality situated in the Schwarzwald-Baar region of Baden-Württemberg, Germany. Nineteen kilometres south of Donaueschingen, it li ...
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
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
s of partially double-stranded, partially single stranded circular DNA (pdsDNA). 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 (DR) segment that pairs the two strands together. In replication, the viral pdsDNA is converted in the host cell nucleus to covalently-closed-circular DNA (cccDNA) by the viral polymerase. Replication involves an RNA intermediate, as in viruses belonging to group VII of
Baltimore classification Baltimore classification is a system used to classify viruses based on their manner of messenger RNA (mRNA) synthesis. By organizing viruses based on their manner of mRNA production, it is possible to study viruses that behave similarly as a d ...
. Four main
open reading frames In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
are encoded (ORFs) 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

Members of the family ''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 (the only other human-pathogenic virus family encoding a polymerase with this capability is ''
Retroviridae A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...
''), RNAse activity (used when the DNA genome is synthesized from pgRNA that was packaged in virions for replication to destroy the RNA template and produce the pdsDNA genome), and DNA-dependent-DNA-polymerase activity (used to create cccDNA from pdsDNA in the first step of the replication cycle).


Envelope proteins

The hepatitis envelope proteins are composed of subunits made from the viral preS1, preS2, and S genes. The L (for "large") envelope protein contains all three subunits. The M (for "medium") protein contains only preS2 and S. The S (for "small") protein contains only S. The genome portions encoding these envelope protein subunits share both the same frame and the same stop codon, generating nested transcripts on a single open reading frame. The pre-S1 is encoded first (closest to the 5' end), 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 (which they transcribe back into cDNA using reverse transcriptase). 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 In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. 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 (called covalently-closed-circular DNA or cccDNA). The genome then undergoes
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
by the host cell RNA polymerase and the pregenomicRNA (pgRNA) 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.


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.


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 (see
host switch In parasitology and epidemiology, a host switch (or host shift) is an evolutionary change of the host specificity of a parasite or pathogen. For example, the human immunodeficiency virus used to infect and circulate in non-human primates in West- ...
). Endogenous hepatitis B virus genomes have been described in crocodilian,
snake Snakes are elongated, limbless, carnivorous reptiles of the suborder Serpentes . Like all other squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales. Many species of snakes have skulls with several more j ...
and
turtle Turtles are an order of reptiles known as Testudines, characterized by a special shell developed mainly from their ribs. Modern turtles are divided into two major groups, the Pleurodira (side necked turtles) and Cryptodira (hidden necked t ...
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.


Nackednaviridae

A proposed family of viruses – the ''Nackednaviridae'' – has been isolated from fish. This family has a similar genomic organisation to that of members of the family ''Hepadnaviridae''. These two families separated over , suggesting an ancient origin for the family ''Hepadnaviridae''. Viruses in the family have non-enveloped, isosahedral structure with T=3 symmetry, smaller than typical ''Hepadnaviridae'' virions (about 5% of the latter show a T=3 symmetry). The circular, monopartite genome is about 3 kb much like ''Hepadnaviridae''. The envelop protein S is accordingly not present, likely the ancestral state by sequence analysis. Unlike ''Hepadnaviridae'' viruses that usually diverge alongside their hosts, viruses in the family jump hosts more frequently. The "type" for this family is ''African cichlid nackednavirus'' (ACNDV), formerly ''African cichlid hepadnavirus'' (ACHBV), a proposed and not-yet-accepted species.


Cell tropism

Hepadnaviruses, as their "hepa" name implies, infect liver cells and cause hepatitis. This is true not only of the human pathogen Hepatitis B Virus but also the hepadnaviruses that infect other organisms. The "adhesion" step of the dynamic phase—in which an exterior viral protein stably interacts with a host cell protein—determines cell tropism. In the case of HBV the host receptor is human sodium taurocholate receptor ( NTCP), a mediator of bile acid uptake, and the virus anti-receptor is the abundant HB-AgS envelope protein.


See also

*
Transmission of hepadnaviruses The transmission of hepadnaviruses between their natural hosts, humans, non-human primates, and birds, including intra-species host transmission and cross-species transmission, is a topic of study in virology. Hepadnaviruses are a family of viruse ...


Notes


References


External links


ICTV Report: ''Hepadnaviridae''


* {{Taxonbar, from=Q1356878 Virus families