View source for Hepadnaviridae

{{Short description|Family of viruses}}
{{Use dmy dates|date=April 2017}}
{{Virusbox
| image = Hepatitis B virus 1.jpg
| image_alt = TEM micrograph showing Hepatitis B virus virions
| image_caption = [[Transmission electron microscopy|TEM]] [[micrograph]] showing ''Hepatitis B virus'' virions
| taxon = Hepadnaviridae
| subdivision_ranks = Genera
| subdivision_ref = <ref>{{cite web |title=Virus Taxonomy: 2018b Release |url=https://ictv.global/taxonomy |website=International Committee on Taxonomy of Viruses (ICTV) |access-date=14 March 2019 |language=en |date=February 2019}}</ref>
| subdivision =
* ''[[Avihepadnavirus]]''
* ''[[Orthohepadnavirus]]''
* ''[[Herpetohepadnavirus]]''
* ''[[Metahepadnavirus]]''
* ''[[Parahepadnavirus]]''
}}

'''''Hepadnaviridae'''''{{efn|Etymology – portmanteau of ''hepa'' (liver: reference to Hepatitis B the primary human member) [[DNA]] virus.}} is a family of [[viruses]].<ref>{{cite journal |last1=Magnius |first1=L |last2=Mason |first2=WS |last3=Taylor |first3=J |last4=Kann |first4=M |last5=Glebe |first5=D |last6=Dény |first6=P |last7=Sureau |first7=C |last8=Norder |first8=H |last9=ICTV Report Consortium |title=ICTV Virus Taxonomy Profile: ''Hepadnaviridae''. |journal=The Journal of General Virology |date=June 2020 |volume=101 |issue=6 |pages=571–572 |doi=10.1099/jgv.0.001415 |pmid=32416744|pmc=7414443 |doi-access=free }}</ref> Humans, apes, and birds serve as natural hosts. There are currently 18 species in this family, divided among 5 genera.<ref name="ICTVReport">{{cite web |title=ICTV Report Hepadnaviridae |url=http://www.ictv.global/report/hepadnaviridae}}</ref> Its best-known member is  [[hepatitis B virus]]. Diseases associated with this family include: [[liver]] infections, such as hepatitis, hepatocellular carcinomas (chronic infections), and cirrhosis.<ref name=ICTVReport/><ref name=ViralZone>{{cite web|title=Viral Zone|url=http://viralzone.expasy.org/all_by_species/9.html|publisher=ExPASy|access-date=15 June 2015}}</ref> It is the sole accepted family in the order '''''Blubervirales'''''.

==Taxonomy==
The following genera are recognized:{{citation needed|date=November 2022}}
* ''[[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|Hepatitis B Virus (HBV)]] was identified as an infection distinct from Hepatitis A through its contamination of [[yellow fever vaccine#History|yellow fever vaccine]]. The vaccine contained human serum as a stabilizing agent which was HBV-infected.<ref>{{Cite web |title=World War II Hepatitis Outbreak Was Biggest in History |url=https://apnews.com/article/ce911d4f173f1c8ade810969005b9e57 |access-date=2023-06-21 |website=AP NEWS |language=en}}</ref> 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.  [[Hepatitis B virus|HBV]] was first identified in the lab as the "Australia agent" by [[Baruch Samuel Blumberg|Blumberg]] and colleagues in the blood of an Aboriginal transfusion patient. This work earned Blumberg the 1976 Nobel Prize in Medicine.{{citation needed|date=November 2022}}

==Genome==
[[Image:HBV Genome.svg|thumb|The genome organisation of HBV; the genes overlap]]

Hepadnaviruses have very small [[genome]]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.{{citation needed|date=November 2022}}

Replication involves an [[RNA]] intermediate, as in viruses belonging to group VII of [[Baltimore classification]]. Four main [[open reading frames]] are encoded (ORFs) and the virus has four known genes which encode seven proteins:  the core capsid protein, the [[Hepatitis B virus DNA polymerase|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.{{citation needed|date=November 2022}}

===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]]''), 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).{{citation needed|date=November 2022}}

===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.{{citation needed|date=November 2022}}

==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.<ref>{{cite journal | vauthors = Shin MK, Lee J, Ryu WS | title = A novel cis-acting element facilitates minus-strand DNA synthesis during reverse transcription of the hepatitis B virus genome | journal = Journal of Virology | volume = 78 | issue = 12 | pages = 6252–62 | date = June 2004 | pmid = 15163718 | pmc = 416504 | doi = 10.1128/JVI.78.12.6252-6262.2004 }}</ref>  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 (called covalently-closed-circular DNA or cccDNA). The genome then undergoes [[Transcription (genetics)|transcription]] 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.{{citation needed|date=November 2022}}

{| class="wikitable sortable" style="text-align:center"
|-
! 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&nbsp;nm. Genomes are circular, around 3.2kb in length. The genome codes for 7 proteins.<ref name=ICTVReport/><ref name=ViralZone />

{| class="wikitable sortable" style="text-align:center"
|-
! Genus !! Structure || Symmetry !! Capsid !! Genomic arrangement !! Genomic segmentation
|-
|''Avihepadnavirus''||Icosahedral||T=4||Enveloped||Circular||Monopartite
|-
|''Orthohepadnavirus''||Icosahedral||T=4||Enveloped||Circular||Monopartite
|}

==Evolution==
Based on the presence of viral genomes in bird DNA it appears that the hepadnaviruses evolved >{{Ma|82}}.<ref name=Suh2013>{{cite journal | vauthors = Suh A, Brosius J, Schmitz J, Kriegs JO | title = The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B viruses | journal = Nature Communications | volume = 4 | pages = 1791 | year = 2013 | pmid = 23653203 | doi = 10.1038/ncomms2798 | bibcode = 2013NatCo...4.1791S | doi-access = free }}</ref> Birds may be the original hosts of the ''Hepadnaviridae'' with mammals becoming infected after a bird (see [[host switch]]).

Endogenous hepatitis B virus genomes have been described in [[crocodile|crocodilian]], [[snake]] and [[turtle]] genomes.<ref name=Suh2014>{{cite journal | vauthors = Suh A, Weber CC, Kehlmaier C, Braun EL, Green RE, Fritz U, Ray DA, Ellegren H | title = Early Mesozoic coexistence of amniotes and hepadnaviridae | journal = PLOS Genetics | volume = 10 | issue = 12 | pages = e1004559 | date = December 2014 | pmid = 25501991 | pmc = 4263362 | doi = 10.1371/journal.pgen.1004559 | doi-access = free }}</ref> This suggests that these viruses have infected vertebrates for over {{Ma|200}}.{{citation needed|date=November 2022}}

Hepadnaviruses have been described in fish and amphibians also.<ref name=Dill2016/> This suggests that this family has co-evolved with the vertebrates.{{citation needed|date=November 2022}}

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.<ref name=Lauber2017a>{{cite journal | vauthors = Lauber C, Seitz S, Mattei S, Suh A, Beck J, Herstein J, Börold J, Salzburger W, Kaderali L, Briggs JA, Bartenschlager R | title = Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses | journal = Cell Host & Microbe | volume = 22 | issue = 3 | pages = 387–399.e6 | date = September 2017 | pmid = 28867387 | pmc = 5604429 | doi = 10.1016/j.chom.2017.07.019 }}</ref>

=== 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 {{Ma|400}}, suggesting an ancient origin for the family ''Hepadnaviridae''.<ref name="Lauber2017a"/>

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.<ref name="Lauber2017a"/> The "type" for this family is ''African cichlid nackednavirus'' (ACNDV), formerly ''African cichlid hepadnavirus'' (ACHBV), a proposed and not-yet-accepted species.<ref name=Dill2016>{{cite journal | vauthors = Dill JA, Camus AC, Leary JH, Di Giallonardo F, Holmes EC, Ng TF | title = Distinct Viral Lineages from Fish and Amphibians Reveal the Complex Evolutionary History of Hepadnaviruses | journal = Journal of Virology | volume = 90 | issue = 17 | pages = 7920–33 | date = September 2016 | pmid = 27334580 | pmc = 4988138 | doi = 10.1128/JVI.00832-16 }}</ref>

==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.<ref>{{cite journal | vauthors = Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W | title = Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus | journal = eLife | volume = 1 | pages = e00049 | date = November 2012 | pmid = 23150796 | pmc = 3485615 | doi = 10.7554/eLife.00049 | doi-access = free }}</ref>

==See also==
* [[Transmission of hepadnaviruses]]

==Notes==
{{Notelist}}

==References==
{{Reflist|32em}}

==External links==
{{Commons category}}
{{Wikispecies}}
* [http://www.ictv.global/report/hepadnaviridae '''ICTV Report:''' ''Hepadnaviridae'']
* [http://viralzone.expasy.org/all_by_species/9.html '''Viralzone''': ''Hepadnaviridae'']
* {{cite web |title=''Hepadnaviridae'' |work=NCBI Taxonomy Browser |url=https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10404 |id=10404}}

{{Viruses}}
{{Baltimore classification}}
{{Taxonbar|from=Q1356878}}
{{Authority control}}

[[Category:Hepadnaviridae| ]]
[[Category:Virus families]]