|TEM micrograph showing hepatitis B virions|
|Group:||Group VII (dsDNA-RT)|
There are two recognized genera:
- Genus Orthohepadnavirus; type species: Hepatitis B virus
- Genus Avihepadnavirus; type species: Duck hepatitis B virus
The name of the family comes from hepa(for HEPAtic)-DNA-virus. "Hepad" means "liver" and is a reference to the family's primary human-pathogenic virus: Hepatitis B Virus.
History and Discovery
Although liver diseases transmissible among human populations were identified early in documented medical history, the first known hepatitis with a viral etiological agent was Hepatitis A in the Picornaviridae family. Hepatits 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 40s. These vaccines contained HBV-infected human serum as a stabilizing agent. HBV was identified as a new DNA virus in the 1960s, followed only a few 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.
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 (DR) segment that pairs the two strands together. In replication, this pds genome is converted in the host cell nucleus to covalently-closed-circular DNA (cccDNA) by the viral polymerase.
As it is a group 7 virus, replication involves an RNA intermediate. Four main open reading frames are encoded (ORFs) and the virus has four known genes which encode seven proteins: the capsid protein, the viral polymerase, surface antigens--preS1, preS2, and S, the X protein and HBsEAg. 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.
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).
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 subuntis 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.
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. 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 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.
Based on the presence of viral genomes in bird DNA it appears that the Hepatoviruses evolved > Birds may be the original hosts of the Hepatovirus with mammals becoming infected after a bird -> mammal host shift..
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 asialoglycoprotein receptor (ASGPR), a mediator of liver cell glycoprotein uptake, and the virus anti-receptor is the abundant HB-AgS envelope protein.
- A Novel cis-Acting Element Facilitates Minus-Strand DNA Synthesis during Reverse Transcription of the Hepatitis B Virus Genome by Myeong-Kyun Shin, Jehan Lee and Wang-Shick Ryu in Journal of Virology (2004) volume 78, pages 6252–6262.
- Suh A, Brosius J, Schmitz J, Kriegs JO (2013) The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B viruses. Nat Commun 4:1791. doi: 10.1038/ncomms2798
- Treichel U1, Meyer zum Büschenfelde KH, Dienes HP, Gerken G.(1997) Receptor-mediated entry of hepatitis B virus particles into liver cells. Arch Virol. 1997;142(3):493–8.