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also associated the presence of the Australia antigen with and the acquisition of this X protein could have been
chronic liver diseases such as cirrhosis and hepatocellular an essential factor for the evolution of hepadnaviruses
carcinoma (HCC). [6,7] Finally, the discovery of the Australia from avian into mammalian hosts. [13] Genomic diversity
antigen also facilitated the eventual development of a between species of hepadnaviruses is reviewed in detail
vaccine that has greatly reduced the global burden of in the literature. [11,17]
HBV infection, [8-10] and Baruch Blumberg was awarded the
1976 Nobel Prize in Medicine for his discovery of HBV. While significant genomic diversity exists between viral
species and particularly between the hepadnaviridae
Despite the decades of work between the discovery of genera, all hepadnaviruses share a large number of
HBV and our current understanding of the virus, many common features. Among these, all members have an
aspects of the HBV life cycle and pathogenesis remain extremely small (3.0-3.3 kb) and compact DNA genome
unclear. The fact that it is estimated that as much as a that encodes overlapping open reading frames (ORFs).
third of the world’s population has been infected with Additionally, all hepadnaviruses use a genome replication
HBV at some point, that roughly 5% of the population strategy in which the virus replicates its DNA genome by
(350-500 million people) are chronically infected with the reverse transcription of an RNA intermediate using the
virus, and that about 800,000 people die annually from reverse-transcriptase activity of the viral polymerase.
acute or chronic HBV-related consequences underscores Hepadnaviruses are also distinguished from nearly all
the importance of a more complete understanding of other viruses utilizing reverse transcription for viral
HBV biology and pathogenesis. [11,12] replication by a number of unique features, including
envelopment of a DNA genome, rather than RNA, and the
HEPADNAVIRIDAE fact that integration of the hepadnavirus DNA genome
into the host-cell genome is not required for viral
While the discovery of human HBV, hereafter denoted as replication. These features, common to all members of
HBV, occurred in the 1960s, recent research has shown the hepadnavirus family, contributed to the designation
that hepatitis B viruses have actually been present since of Hepadnaviridae as a distinct family of viruses. [11]
the time of the dinosaurs. In fact, the earliest known
hepatitis B virus is approximately 82 million years old HBV
and was identified from the DNA of infected birds from
[13]
the Mesozoic period. Although multiple theories of Studies have identified a minimum of eight HBV genotypes,
the origins of HBV exist, it appears that the infection of designated A-H, with genetic differences greater than
mammals is a much more recent event. The jump into 8%, but less than 17% between each genotype. [11,17,18] Two
humans, in particular, may have been only about 40,000 additional potential genotypes have been described.
years ago. Despite the evolutionary timeline, modern Genotype I has genetic divergence around 8% with a strong
[14]
HBV is remarkably similar to these ancient hepatitis B homology to genotype C, making its classification as a
[19]
viruses. [13] distinct genotype more controversial than that of the more
well-accepted genotypes. A potential 10th genotype,
[20]
The present day Hepadnaviridae family is a group of small, genotype J, has also been described recently and is likely
hepatotropic, DNA viruses that are divided into two distinct the result of recombination of genotype C and gibbon HBV. [18]
genera based on their divergent genomic sequences and
narrow host range of infection. The avihepadnaviruses, There is a distinct distribution of HBV genotypes within
such as duck HBV (DHBV) and heron HBV, infect birds. specific populations and geographic locations. Similarly,
In contrast, the orthohepadnaviruses infect mammals there is an association between genotype and disease
and include HBV and woodchuck hepatitis virus (WHV), severity and outcome. In the United States, where chronic
among others. Each member of the Hepadnaviridae family HBV infection is relatively uncommon, each genotype is
is primarily species specific. For example, the only non- present, though not at equal levels. Within the United
human hosts of HBV are chimpanzee and treeshrew, each States population, genotypes A and D are most prevalent
of which can be experimentally infected. [15,16] Additionally, overall, and the distribution of genotypes can be further
a primate virus similar to HBV, called woolly monkey HBV, divided based on ethnicity. [21,22] For example, genotype
has been identified in woolly monkeys and designated C is most common in Asian Americans, which correlates
as the prototype of a new species of hepatitis B-like with the prevalence of this genotype in much of Asia. This
viruses. A maximum of 40% sequence divergence exists is significant because genotype C has been associated
between orthohepadnaviruses, while only 20% sequence with a more severe disease and a lower response rate to
divergence exists among avihepadnaviruses; however, interferon therapy. [23,24]
little to no homology exists between the two genera.
All mammalian HBV encode an X protein, which has HBV GENOME ORGANIZATION
been shown to be required for viral replication and has
oncogenic properties (discussed below). This X protein HBV has a small (3.2 kb), partially double-stranded,
is either lacking or highly divergent in avian viruses, relaxed-circular DNA genome that encodes four
164 Hepatoma Research | Volume 2 | July 1, 2016