Genus Orthohepadnavirus

Type Species	Hepatitis B virus	(HBV)

Distinguishing Features

Viruses of this genus infect mammals, with a narrow host range for each virus species. The only known natural host of HBV is humans, although chimpanzees may be infected experimentally and there are also reports of experimental transmission to African green monkeys, rhesus and woolly monkeys. Virions of HBV are 40-45  nm in diameter with a 32-36  nm internal nucleocapsid, and empty envelope particles of HBV are typically spherical (16-25  nm diameter) and filamentous (20  nm diameter and variable in length). The genome of HBV is 3.2  kb with a cohesive overlap of 240  bp. The viruses have an S protein of approximately 226 amino acids as a major envelope protein, a non-essential M protein of about 271 amino acids and an L protein of approximately 400 amino acids.

The proteins are partially glycosylated, thus generating doublets in gel electrophoresis, eg for HBV, P24/GP27 for S, P39/GP42 for L, and, in the case of M, GP33/GP36 due to an additional glycosylation at the N-terminal end. The HBV core protein is approx 180 amino acids, and the virus encodes an HBx protein of cc 154 amino acids whose natural function is unknown.

At least 5 antigenic specificities have been identified for HBsAg. A group determinant (a) is shared by virtually all HBsAg preparations. Mutations in this region have been found in immunised individuals who subsequently become infected, in HBV carriers and infected individuals given immunotherapy. Two pairs of subtype determinants (d,y and w,r) have been demonstrated which are generally mutually exclusive (and thus usually behave as alleles). Antigenic heterogeneity of the w determinant, and additional determinants such as q, x or g have also been described. Thus, eight major serological subtypes are found (ayw, ayw₂, ayw₃, ayw₄, ayr, adw₂, adw₄ and adr); they have distinct geographical distributions with some overlap. Sequence analysis of the surface gene has also been used to distinguish genotypes or clades A-F that differ between each other by 8-14% at the nucleotide level. Different genotypes also have different geographical distributions, and there is some but not complete correspondence between genotype and serological subtype.

Different isolates of WHV show < 3.5% nucleotide sequence variation. A virus of arctic ground squirrels (Arctic squirrel hepatitis virus, ASHV) differs from WHV and Ground squirrel hepatitis virus (GSHV) to about the same extent (about 15% base changes) as these two latter viruses differ from each other.

Biological Properties

HBV may cause acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma, immune complex disease, polyarteritis, glomerulonephritis, infantile papular acrodermatitis and aplastic anemia. An asymptomatic carrier state with high viremia may develop particularly after perinatal infection or under immune suppression.

Horizontal transmission of HBV usually occurs by : (1) percutaneous contact with infected blood or body fluids, eg., intravenous drug abuse, use of infected blood or blood products ; (2) sexual contact; (3) perinatal transmission from an infected mother; (4) “inapparent horizontal” transmission, particularly between children in low socio-economic communities and thought to be at least in part due to unrecognised exposure to open skin breaks or mucous membranes. In communities with a high prevalence of infection, routes (3) and (4) predominate, while in low prevalence communities infections are acquired later in life and involve particularly routes (1) and (2).

Hepatitis occurs in woodchucks and squirrels infected with their respective viruses, and chronic infection leads to a risk of hepatocellular carcinoma even greater than that in chronic carriers of HBV. In the case of WHV, hepatocellular carcinoma frequently occurs within 2 years of infection.

List of Species Demarcation Criteria in the Genus

The species demarcation criteria in the genus are:

	Nucleotide sequence diversity; WHV/HBV 40%; GHSV/WHV 15%
	Differences in host range: HBV infection is limited to primates; GSHV infection has been experimentally transferred to chipmunks and woodchucks but not to several related ground squirrel species; WHV also has a narrow host range, being reported not to infect ground squirrels or other rodent species.
	Oncogenicity: All three virus species are associated with primary liver cancer in infected hosts. However, proposed mechanisms are different in each case and the incidence and typical time scales differ, being highest with WHV and lowest with HBV.

A number of other viruses have been isolated from subhuman primates (chimpanzees, gibbons, woolly monkeys) and from various rodent species (Artic ground squirrels, Richardson’s ground squirrels) but currently available data does not allow distinction of these as separate species using the above criteria.

List of Species in the Genus

Official virus species names are in italics. Tentative virus species names, alternative names ( ), strains or serotypes are not italicized. Virus names, genome sequence accession numbers [ ], and assigned abbreviations ( ) are:

Species in the Genus

Ground squirrel hepatitis virus	[K02715]	(GSHV)
Hepatitis B virus	[M12906, J02202-3, J02205, X01587, X02763, X65257]	(HBV)
Woodchuck hepatitis virus	[J02442, J04514, M11082, M18752, M60764, M90520]	(WHV)

Tentative Species in the Genus

Arctic squirrel hepatitis virus	(ASHV)