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hepadnavirus family can only directly infect hepatocytes vaccine testing. [167-170] The ethical issues and high costs
within the liver of their respective avian or mammalian associated with non-human primate use, however, have
hosts or cultured, well-differentiated primary hepatocytes limited the use of this model and the recent reevaluation
that are derived from these hosts. This has hampered in the United States (one of only two countries to allow
the capabilities of researchers to study a natural HBV chimpanzee research) of the need for chimpanzees in
infection. An overview of the in vivo model systems that preclinical research [171] will likely diminish their future use
exist for studying HBV biology is provided below. even further.

Due to the limited host range of HBV, few suitable A number of mouse models exist for the study of
animal models exist for studying an in vivo HBV infection. HBV, and have been reviewed more extensively in
[60]
Closely related viruses, such as DHBV and WHV, [141] have the literature. [157,172] Typically these models can be
been used in their respective host animals as surrogate separated into two categories: HBV-/HBx-tg mice, which
models for understanding overall hepadnavirus biology. constitutively express HBV or HBx, respectively, and mice
These studies have been instrumental in establishing that are delivered the HBV genome or an HBx-expressing
our understanding of the viral life cycle, including plasmid by hydrodynamic tail-vein injection. Although
the identification of DNA replication through an RNA mouse hepatocytes cannot be directly infected with HBV,
intermediate, the establishment of a pool of cccDNA as the use of tail-vein-delivered DNA or HBV-tg mice allows
[61]
a mechanism for maintaining chronic infection, [142,143] and studies of the impact of HBV replication on hepatocyte
the course of both acute [144-146] and chronic [147-149] infection. physiology; HBx-tg mice similarly aid in the study of HBx-
mediated effects. While these mouse models are valuable
The treeshrew, Tupaia belangeri, is a small animal tools, they do have their drawbacks. For example, there
model and is one of the very few animals that can be is no inflammatory response against HBV in an HBV-tg
experimentally infected with HBV. [150] Genomic analysis mouse, which could alter the cellular pathways activated
has placed the treeshrew phylogenetically between in these models compared to a natural HBV infection.
humans and rodents, [151,152] and this similarity to primates Additionally, because some HBV-tg mice do not produce
has spurred its use as a model for a broad range of studies, HBV cccDNA, there is some concern over whether this
including as a model for viral hepatitis. [16,153] Specifically, system accurately mimics all aspect of HBV replication
Tupaia belangeri has been used as a model to study the in humans. [112] Despite this, mouse models have been
immediate effects of HBV infection on gene expression in instrumental in determining a number of important
the liver and to identify genes potentially contributing aspects of the HBV life cycle, including the requirement
[16]
to the development of HBV-associated HCC. [154] In fact, [26]
freshly isolated primary treeshrew hepatocytes were for HBx in HBV replication and the oncogenic potential
[173]
[89,91]
recently used in multiple studies in which hNTCP was of HBV and HBx.
identified as the HBV receptor. [42,155] Recent studies also
suggest that neonatal exposure of treeshews to HBV can More recently, two additional mouse models have been
lead to a disease progression similar to what is seen in described that may greatly enhance our understanding
humans, with development of a chronic infection leading of the HBV life cycle and HBV-associated disease. The
to the eventual development of HCC. [156] Unfortunately, first of these systems is the humanized mouse model,
a relatively low HBV infection efficiency and lack of in which the majority of the mouse liver is repopulated
genetically uniform tree shrew strains has limited their with either primary human hepatocytes or human
use. [157] induced pluripotent stem cells. The use of these animals
represents a significant advancement, as they support
The chimpanzee is the only non-human primate model for direct infection with HBV and can develop a chronic HBV
HBV infection and, along with the tree shrew, represents infection, [174,175] thereby allowing studies of the impact
one of the only animal models that can be directly infected of an HBV infection on the liver in a cellular context
with HBV. HBV can establish both acute [158] and chronic more similar to that seen in the human liver. Some of
infections [159] in chimpanzees, and this model has been these chimeric mouse models include both a humanized
used most often for modeling the immune response to liver and humanized immune cells, offering the unique
HBV and the interaction between the virus and host. [160- opportunity to study the human immune response in a
164] Studies in chimpanzees have helped to establish the small animal model. Although different techniques for
relationship between the innate and adaptive immune the development of the humanized mouse model exist,
response to HBV infection, demonstrating minimal early a number of groups have adapted their use for the study
activation of innate immune mediators [160] and a reliance of HBV. These studies cover a broad range of aspects
on CD8+ T cells for viral clearance through interferon γ- of HBV biology, including studies of the HBV-mediated
and tumor necrosis factor α-dependent mechanisms, [161] immune response, [175,176] investigation of potential HBV
in agreement with previous work in HBV-tg mice. [165,166] therapeutics, [177,178] and aspects of the HBV life cycle such
Another important use of the chimpanzee model has as particle formation, [179] receptor binding, [180] and cccDNA
been as a surrogate model for preclinical drug and regulation. [181]
Hepatoma Research | Volume 2 | July 1, 2016 171