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Hepatitis B virus

Hepatitis B virus (HBV) is a partially double-stranded DNA virus,[1] a species of the genus Orthohepadnavirus and a member of the Hepadnaviridae family of viruses.[2][3] This virus causes the disease hepatitis B.[4]

For the disease, see Hepatitis B.

(hepatitis B surface antigen) was the first hepatitis B virus protein to be discovered.[15] It consists of small (S), medium (M) and large (L) protein.[16]

HBsAg

(hepatitis B core antigen) is the main structural protein of HBV icosahedral nucleocapsid and it has function in replication of the virus.[17] Capsid formation is the main factor for infection of the cell.[18] HBcAg contributes to HBV clearance in vivo, but it is unknown whether HBcAg has to be in the capsid form to contribute to viral clearance.[19]

HBcAg

is incorporated into the nucleocapsid along with the pre-genomic RNA (pgRNA). Inside the capsid, the pgRNA undergoes reverse transcription, making the (-) DNA strand. At the same time, most of the RNA template is degraded by the RNase activity of the polymerase. This is followed by (+) DNA strand synthesis, and the polymerase ends up covalently bound to the (-) DNA strand.[20][21] The polymerase is discarded after the virion infects a new cell.

Hepatitis B virus DNA polymerase

(hepatitis B envelope antigen) can be found between the icosahedral nucleocapsid core and the lipid envelope, but is considered "nonparticulate" and is secreted and accumulates in serum. HBeAg and HBcAg are made from the same reading frame.[22]

HBeAg

is small,[23] 154 amino acids long, nonstructural and has an important role in HBV-associated liver disease and in HBV replication in HepG2 cells. Many activities have been linked to expression of HBx. However, the molecular mechanisms of many of these activities are unknown.[24] This protein is multifunctional and it activates cellular signaling pathways and is essential for viral infection.[25]

HBx

Evolution[edit]

The early evolution of HBV, like that of all viruses, is difficult to establish. The identification of hepadnaviruses in a wide range of vertebrates suggests a long coevolution. The identification of endogenous hepadnaviridae elements shared by various bird species shows the presence of these virus in birds for at least 70M years.[27] Although similar evidence is missing for mammals, the phylogenetic position of orthohepadnaviruses as a sister clade to avihepadnaviruses suggests a presence of the virus in the amniote ancestor and a subsequent coevolution with both birds and mammals after their divergence (>300M years ago). It has also been proposed that a New World bat hepadnavirus may be the origin of the primate hepadnaviruses.[28] Avihepadnaviruses lack the X protein but a vestigial X reading frame is present in the genome of duck hepadnavirus.[29] The X protein may have evolved from a DNA glycosylase.


Recently, the reconstruction of HBV genomes from ancient human remains has allowed investigating the evolution of this virus in humans in more details.[30][31][32] In 2021, a study reconstructed 137 ancient HBV genomes and proved the presence of the virus in humans since at least 10,000 years.[30] The most recent common ancestor of all known human HBV lineages was dated to between 20,000 and 12,000 years ago. However, it cannot be said whether the virus was present in humans long before that or acquired shortly before from another animal species. The evolution of HBV in humans was shown to reflect known events of human history such as the first peopling of the Americas during the late Pleistocene and the Neolithic transition in Europe.[30] These studies also showed that some ancient HBV strains still infect humans, while other became extinct.[30][31][32] HBV strains found in African and South-East Asian apes (chimpanzees, gorillas, orangutans, bonobos and gibbons) appear related to human HBV strains, which could reflect past cross-species transmission events.[33][30]


A study of isolates from the circumpolar Arctic human population has proposed that the ancestor of the subgenotype B5 (the endemic type found in this population) that the ancestral virus originated in Asia about 2000 years ago (95% HPD 900 BC – 830 AD).[34] Coalescence occurred about 1000 AD. This subgenotype spread from Asia initially to Greenland and then spread westward within the last 400 years.

Hepatitis B vaccine

Nucleoside analogues

(cancer virus)

Oncovirus