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Figure 3: The natural history of an hepatitis B virus (HBV) infection. Infection with HBV can result in an acute, self-clearing, or chronic HBV infection; the
development of a chronic HBV infection positively correlates with younger age. A chronic infection usually follows a long-term course in which the virus
replicates at high levels, followed by immune-mediated control of viral replication associated with liver inflammation. Seroconversion and maintenance
of undetectable or low levels of viral replication are markers of a favorable prognosis, but long-term disease can lead to the development of cirrhosis and
hepatocellular carcinoma. (See text for additional details)
Another recently described mouse model expresses summary of the available cell culture model systems that
hNTCP to allow receptor binding by HBV. Currently these are used to study HBV biology, each one possessing its
mice are limited in their utility for studying HBV, as own benefits and limitations.
multiple groups have shown that while HBV can bind to
hNTCP expressed in mouse cells, the HBV life cycle does Most hepatocyte cell lines that are used in HBV-related
not appear to proceed beyond receptor binding. [103,182,183] studies are tumor-derived and thus are transformed. Since
Conversely, HDV utilizes HBV envelope proteins for its cellular signaling pathways are significantly altered in
envelopment, and hNTCP-expressing mice have been cancer, cell lines derived from tumors do not recapitulate
used for the study of HDV infection. [184] Further work the physiology of normal hepatocytes. While the results
with hNTCP-expressing systems may help to determine obtained by using transformed cell lines may be valid in
species-specificity factors that could ultimately lead to a specific cellular context, caution should be exercised
the development of an hNTCP-expressing mouse model in the interpretation of such results because they may
useful for the study of HBV infection. Together with not necessarily represent the effects of HBV on cellular
the humanized-liver model, these mouse models could physiology in normal, untransformed hepatocytes, the
greatly contribute to our understanding of the early authentic site of an HBV infection. In addition to tumor-
stages of an HBV infection, including entry, HBV genome derived cell lines, some cell lines have been specifically
transport to the nucleus, and genome repair. derived from HBV-positive tumors. Examples of cell lines
isolated from HBV-positive tumors include the PLC/PRF/5
The paucity of in vivo models for studying direct HBV cell line and the Hep3B cell line, which are human HCC-
infections, and the limited availability of cultured derived cell lines containing multiple copies of HBV DNA
primary human hepatocytes, has lead many researchers integrated into the host DNA. While the PLC/PRF/5 [187] and
to study HBV replication and the activities of HBV- the Hep3B [188] cells are active in HBsAg production, they
encoded proteins in immortalized or transformed liver do not produce HBV virions and display no indicators of
cell lines and in cultured primary hepatocytes derived HBV replication, [187,189-192] so results of studies using these
from small-animal models such as rats or mice. [11,92] Use of cell lines require careful interpretation.
these systems necessitates bypassing the initial receptor-
mediated infection of the cell by direct transfection of In an attempt to establish a system to study the biology
the HBV DNA genome. Although primary hepatocytes of HBV, and specifically HBV replication, the results of
derived from small-animal models, namely rat and mouse, numerous studies demonstrated that HBV DNA could be
cannot be directly infected with HBV, they can support transfected into many different cell lines, including the
HBV replication and serve as a surrogate model system hepatoblastoma-derived cell line HepG2 [15,193] and the
for studying the effects of HBV replication and HBV hepatoma-derived cell line Huh7 [188,194,195] and that HBV
proteins on cellular physiology. [86,185,186] Here we provide a could replicate efficiently in these cells. Consequently,
172 Hepatoma Research | Volume 2 | July 1, 2016