Transmission of hepadnaviruses

Hepadnaviridae

A family of viruses which can cause liver infections in humans and animals. There are two recognized genera:

Hepadnaviruses are Group VII viruses that possess double-stranded DNA genomes and replicate using reverse transcriptase. This unique replication strategy, plus they have extremely small viral genome, and a very narrow host range and tissue tropism, make it designated as family hepadnaviridae.

Structure

With the example of human HBV: the particular feature of the HBV structure is the presence of three different forms in the plasma of infected patients:

Genome

As with the example of HBV, showing in figure 2, four open reading frames are encoded (ORFs), all ORFs are in the same direction, defining the minus- and plus-strands. And the virus has four known genes, which encode the core protein, the virus polymerase, surface antigens (preS1, preS2, and S) and the X protein. The minus-strand DNA is complete and spans the entire genome, while the plus strand spans only about two-third of the genome length and have variable 3’ ends. But for the avihepadnaviruses they normally extend plus-strands almost all the way to the modified 5’ end. The minus-strand is linked to the viral reverse transcriptase and can encode all the known viral proteins, but the plus-strain cannot encode viral proteins.

Replication

With the example of HBV: the mechanisms of infecting hepatocytes are still not well understood, but among the studies, it was revealed that the PreS1 domain of the L protein, plays a critical role in the infection, thus exhibiting different host specificity between different hepadnaviruses. Figure show the general process of the HBV infecting host cell: attachment-entry-uncoating-replicate-assembly-release. About the viral entry, several proteins have been identified as possible virus receptors, and studies show that the binding of virion with receptors can be neutralized by anti-PreS1 antibodies.

The replication is the unique reverse transcriptase strategy: after uncoating, nucleocapsids are transported to the host cell nucleus, the virion DNA will be converted into covalently closed circular (CCC) DNA, the template for the transcription of the viral RNAs. Then undergoes transcription by the host cell RNA polymerase and the transcript is translated by host cell ribosomes; the high capacity of this replicating part contributes many errors which may help the virus adapt to the host.

New virus particles are formed, which acquire lipid from the endoplasmic reticulum of the host cell, and the genome is packaged within these particles, which then bud off from the cell; and some part of the new genome may return to the host cell nucleus for replication more genomes.

Phylogenetic tree

All the members of family hepadnaviridae share remarkable similarities in the genome organization and the replication strategies, however, it also shows the differences between different species, different genotypes, and different subtypes. The species specificity of them are determined, to some extent, at the level of virus entry, involving the PreS1 part of the large envelop protein L, which could be a reason for their specificity of host range.

Orthohepadnavirus

Viruses in this genus infect mammals, including human, apes, and rodents, with a narrow host range for each virus. The only known natural host for HBV is human, chimpanzees maybe infected experimentally. The orthohepadnaviruses have been divided into four distinct species, with HBV (human Hepatitis B virus), WHV (Woodchuck Hepatitis virus), GSHV (Ground squirrel hepatitis virus ), and WMHV (Woolly monkey hepatitis virus) as the prototypes, based on the host range from a limited number of studies. From the result of molecular studies about the polymerase chain reaction (PCR)-based assays, information about the number and geographic distribution of HBV genotypes and naturally occurring HBV mutants are gained. Eight HBV genotypes, A to H, have been identified in human and three closely related genotypes in apes are found, like gibbon, orangutan, chimpanzee; and he eight HBV genotypes have further diverged into at least 24 subgenotypes. With different analysis, including analysis of recombinants, the new Genotype J was provisionally assigned to be a genetic variant of HBV which is divergent from known human and ape genotypes, it was isolated from a Japanese patient.

Avihepadnavirus

Viruses of this genus exclusively infect birds; duck hepatitis B virus (DHBV) and heron hepatitis B virus (HHBV) are the prototypes. Avihepadnaviruses have been detected in various duck species. As the same with the orthohepadnaviruses, avihepadnaviruses have a rather narrow host range, but its common host are ducks and geese, other possible hosts are herons, stocks and crane.

The differences between orthohepadnaviruses and avihepadnaviruses

Within human

Till 2000, there are more than 5.2 million cases of acute hepatitis B infection, and chronically infects approximately 5% of the human population. HBV is the most common one among those hepatitis viruses. It can cause chronic infection of liver in humans, which has become a global public health problem, since chronic hepatitis can cause cirrhosis or death from liver failure within certain times. And it is the major cause of HCC, contributing about 60-80% of the HCC cases around the world.

HBV is transmitted by parenteral contact with body fluids, such as blood and lymph; perinatal exposure of infants to carrier mothers. It is thought that mother-to-child perinatal transmission and the establishment of a lifelong highly infectious carrier state are responsible for the observed high rates of endemicity in high-prevalence regions such as South and East Asia and sub-Saharan Africa. In some cases breast milk of HBsAg positive mothers has been found to be positive for the virus, but there have not been any reports of HBV transmission through breast-feeding, even before the availability of hepatitis B vaccine for infants.

Cross-species transmission

Cross-species transmission has not been proven yet, but if this occurs, the chance to eradicate HBV infection by immunization will be diminished due to the difficulty in controlling of natural virus reservoir. And increasing human encroachment on rainforest habitat and fragmentation of declining populations increases the interactions and consequently the risks of disease transmission between wild primates and human populations. Transmission of mammalian hepadnavirus strains between cross-species primate hosts has been found in many cases, recombination of hepadnavirus strains from cross-species primate hosts, further demonstrates that primate associated HBV strains can indeed share hosts in nature, and cross-species transmission of primate-associated HBV strains provides the probability of interspecies recombination.

Within non-human mammals

Between human and non-human mammals

Since the similarity between human and apes, and common ancestors human and apes shared long time ago, there are possibilities to happen transmission of HBVs among them. The prevalence of HBV infection in the natural primate habitat is unknown. Most data resulted from the studies performed on samples obtained from captive animals, wild-born or captive-born. Human HBV infects only humans and closely related primates, such as chimpanzee, chacma baboon, and to some extent, tree shrew, but does not infect woolly monkeys. HBV isolates have been shown to infect gibbon apes and chimpanzees, but not convincing evidence of an infection of macaques or other members of the Cercopithecidea family. Macaca sylvanus is able to replicate HBV in vivo replication in primary macaque hepatocytes. However, susceptibility of these animals has not been shown.

In general, these results imply that nonhuman primate HBV variants may be transmittable to humans. At least they infect representatives of the families Pongidae and Hylobatidae. However, at present it remains to be elucidated if nonhuman primate HBV variants are transmittable to humans and whether they cause disease in humans. And till now, no report of HBV transmission from captive animals to humans currently exists. However the potential for zoonotic disease transmission exists where blood or body fluid exposure is common. Such scenarios could include chronically infected animals kept as family pets, close contact with caretakers, in situations in which chimpanzees are slaughtered and used as bushmeat.

Within birds

Many cases about avihepadnaviruses transmission between or within species have been studied.

Between human and birds

There is no evidence for transmission of avian hepadnavirus between avian and human, but recombination of avihepadnavirus strains between cross-species avian hosts can offer potentials for the transmission between human and bird, considering that many birds are one of the main sources of food for human.

Factors infecting the transmission

The special replication strategy gives this genus a special character, but also the high replication capacity and high error rate of the viral reverse transcriptase, thus HBVs from this genus have the ability to adapt to the host’s environment, and varies from different hepadnaviruses, thus exhibiting species specificities.

Pre S1 regions of the L protein, exhibiting different host specificity, if proteolytically being removed from HBV particles results in a loss of infectivity. The S protein therefore is needed, but not sufficient for HBV entry. In contrast to the M protein, the L protein is essential for the viral infectivity. These special proteins plays different role in different viruses, thus determining the different host ranges, if this were strictly true, we would expect that divergence in pre-S would affect cross-species infection, which then can contribute the different transmission of different hepadnaviruses.

Potentials

A lot of studies have well characterized the horizontal transmission of HBV through parenteral routes and co-infections with different genotypes of HBV have also been reported, including genotypes A and D, genotypes A and G, and genotypes B and C. In Asia, genotypes B and C account for almost all HBV infections. Infection with genotype C may induce more severe liver diseases than infection with genotype B. Recombination between genotypes B and C can occur as the result of co-infection of the two genotypes and recombinant strains may possess an enhanced disease-inducing capacity compared with genotype B. It has also been reported that the predominance of recombinant strains between genotypes B and C might be associated with the development of hepatocellular carcinoma in young carriers in Taiwan.

Though the hepadnaviruses have a very limited host range, with the potential cross-species transmission of hepadnavirus among primates and some families of birds, combined with recombinants, it might change the hepadnavirus host specificity. Interspecies recombination between hepadnaviruses from cross-species hosts would provide a large variation of virus genome, which will change the pathogenicity and transmissibility, and enlarge the host range; the first evidence of potential recombination between Chimpanzee HBV and human HBV genome was documented, recombination between human and non-human primate HBV strains, between GiHBV strains from different genera of gibbons, and between birds HBV strains from different avian sub-families were confirmed. All those experiments provided data allowing us to better understand the background, virus hosts, and zoonotic transmission of the non-human primate HBVs.

Both the co-infection and recombination could change the hepadnaviruses host range, even can enhance the ability of adapting to different host, or to different medical treatment, evolving to different mutants, thus existing great potentials of cross-species transmissions, and what all these could result is to defeat all our trying to decrease the infection of hepadnavirus, and even destroy our confident to get through the influence of being infected by HBV.

A lot more should be done, to decrease the possibility of transmission, thus enhancing human health.