Origins and Evolution of Hepatitis B Virus and Hepatitis D Virus

Abstract

Members of the family Hepadnaviridae fall into two subgroups: mammalian and avian. The detection of endogenous avian hepadnavirus DNA integrated into the genomes of zebra finches has revealed a deep evolutionary origin of hepadnaviruses that was not previously recognized, dating back at least 40 million and possibly >80 million years ago. The nonprimate mammalian members of the Hepadnaviridae include the woodchuck hepatitis virus (WHV), the ground squirrel hepatitis virus, and arctic squirrel hepatitis virus, as well as a number of members of the recently described bat hepatitis virus. The identification of hepatitis B viruses (HBVs) in higher primates, such as chimpanzee, gorilla, orangutan, and gibbons that cluster with the human HBV, as well as a number of recombinant forms between humans and primates, further implies a more complex origin of this virus. We discuss the current theories of the origin and evolution of HBV and propose a model that includes cross-species transmissions and subsequent recombination events on a genetic backbone of genotype C HBV infection. The hepatitis delta virus (HDV) is a defective RNA virus requiring the presence of the HBV for the completion of its life cycle. The origins of this virus remain unknown, although some recent studies have suggested an ancient African radiation. The age of the association between HDV and HBV is also unknown.

Figure 1.

Geographical distribution of the HBV genotypes and subgenotypes. Genotype I and J are not shown as they have not been ratified by the International Committee on Taxonomy of Viruses (ICTV); genotype I is found in Southern China and Vietnam, whereas genotype J was identified from a Japanese soldier who had spent time in Borneo. Subgenotype C3 in the Western Pacific is referring to Melanesian areas, such as the Solomon Islands and Vanuatu. (From Spradling et al. 2013; with permission from the authors.)

Figure 2.

Maximum likelihood (ML) phylogenetic tree showing the genetic relationships between all members of the Hepadnaviridae family. These include 219 complete hepatitis B virus (HBV) genomes determined from primate, rodent, bat, and avian species. Primate HBV sequences were from humans (genotypes A–J), nonhuman primates from Asia (gibbons and orangutans), apes from Africa (chimpanzees and gorilla), and woolly monkey hepatitis B virus (WMHBV). Rodent HBV sequences were from ground squirrel hepatitis virus (GSHV), arctic squirrel hepatitis virus (ASHV), and woodchuck hepatitis virus (WHV), whereas the bat HBV sequences were from Burmese long-fingered bats (LBHBV), African roundleaf bats (RBHBV), African horseshoe bats (HBHBV), and tent-making bats (TBHBV) from Panama. The avihepadnavirus HBV sequences were determined from duck hepatitis B virus (DHBV), Ross goose hepatitis virus (RGHBV), crane hepatitis B virus (CHBV), heron hepatitis B virus (HHBV), stork hepatitis B virus (STHBV), and parrot hepatitis B virus (PHBV). The ML tree was bootstrapped 1000× and only values >50% are shown.

Figure 3.

Diagrammatic representations of recombination among hepatitis B viruses (HBVs). (A) Gibbon HBV and a human genotype C HBV, recombining in the core gene to generate the genotype J. (B) Modular (at least eight) nature of the HBV genome recognized from common HBV recombinants identified to date (Simmonds and Midgley 2005; Bowyer and Sim 2000). Simmonds and Midgley (2005) have identified each one of these as a major phylogenetic discontinuity, which they propose has led to the emergence of the major HBV genotypes recognized today.

Figure 4.

The human family tree updated with the recent recognition of admixtures between the common Homo sapiens lineage with an archaic African (Nigerian) as well as with the Neanderthal and Denisovan lineage. This has become known as the “leaky replacement model” of anatomically modern human (AMH) origins. (From Gibbons 2011; modified, with permission, from the author.)

Figure 5.

Reconstruction of early spread of modern humans outside Africa. YRI, Yoruba; ABR, Australian Aboriginal; CEU, European; HAN, Han Chinese; kyBP, thousand years before present. (From Rasmussen et al. 2011; with permission from the authors.)

Figure 6.

Phylogenetic tree of indigenous samples of HBV full genomes. The Orang Asli sequences form two groups (red): three clustered with C1 sequences, and three did not group with any other subgenotypes of C. The Torres Strait Islanders (blue) form their own clade, which shows a relationship with genotype C14. The Melanesians from Vanuatu clustered with C3 sequence, whereas the HBV from the indigenous Australians (purple) were genotype C4. The tree was generated using the maximum likelihood method. Numbers on branches indicate >50% bootstrap values (from 1000 resamplings).

Figure 7.

Reconstruction of early spread of modern humans outside Africa superimposed with the genotype C trail of HBV isolated from indigenous people along the coastal route. CEU, European; HAN, Han Chinese; ABR, Australian Aboriginal; YRI, Yoruba; GiHBV, gibbon HBV; ChHBV, chimpanzee HBV; kyBP, thousand years before present. (From Rasmussen et al. 2011; modified, with permission, from the authors.)