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binding factor (PBF). [292] Importantly, multiple studies hepatocytes and concomitant hepatocyte regeneration,
have also shown an HBV-mediated decrease in the the activities of certain HBV proteins such as the HBx,
levels of functional miR-122, [291,292,296-299] although the and potential consequences of HBV genome integration
mechanism for this reduction remains unclear. One into the host genome. [92,207]
potential mechanism is a sponge effect, where the HBV
transcripts act as a sponge to divert miR-122 away from Although there are treatments for a chronic HBV infection,
endogenous targets, [291,292] although it is unclear whether resistance to currently available anti-HBV drugs, which
the levels of HBV transcripts in the cell reach the high develops due to the emergence of HBV mutants, is one
levels of target required for this sponge effect to have major drawback of continuing nucleoside analog therapy.
a biological impact. [300] Interestingly, primary tree shrew Moreover, existing antiviral treatments can control but
hepatocytes, which can be directly infected with human not entirely eliminate HBV because of the persistence
HBV, showed an increase in the levels of miR-122 in of HBV nuclear-localized cccDNA, and the persistence
response to HBV infection. [301] Further research will be of cccDNA remains a major obstacle for the treatment
needed to determine if this effect is the result of using a and cure of chronic HBV infections. [316-320] While there has
more biologically relevant system, with direct infection, been substantial progress in identifying mechanisms that
or is an inherent difference between tree shrew and underlie HBV infection, replication and clearance, there
human hepatocytes. are still gaps in our understanding of the HBV lifecycle. The
paucity of cell culture model systems that can recapitulate
Other miRNA families have also been assessed for all the aspects of a human HBV infection and the scarcity
their role in HBV replication, including miRNAs with of in vivo models for studying direct HBV infections has
well-established roles as either oncomirs or tumor impeded our understanding of HBV biology. The recent
suppressors. For example, the let-7 family, which function discovery of hNTCP as the functional HBV receptor has
as tumor suppressor miRNAs and are downregulated in provided new opportunities for the creation of novel cell
multiple cancers including HCC, [302] are decreased in the culture model systems that can be used to understand
context of HBV replication, HBx expression, and HBV- the outcomes of a natural HBV infection. It would also
associated HCC. [303-307] The miR-15 family, [305,307-312] mir-125 be interesting to utilize tg mice expressing a hNTCP to
family, [303,305,310,313,314] miR-17/92 cluster, [289,303,307,310,315] and study HBV biology and examine the activities of HBV-
miR-199a-3p [289] are all HCC-related miRNAs that multiple encoded proteins. However, currently, hNTCP tg mice
groups have studied in the context of HBV. Although the do not permit the establishment of a productive HBV
field is still developing and contradictory reports exist, infection and it is likely that identification of additional
when taken together these reports support the overall species-specific determinants of HBV infection will be
impact of HBV on cellular miRNAs. How these miRNAs required before small rodent models of HBV infection
impact HBV replication, and ultimately HBV-associated and pathogenesis can be fully utilized. [103,182,183] Although
disease and development of HBV-associated HCC, mice with humanized-livers and immune systems provide
remains incompletely understood. another promising model for studying HBV infection and
pathogenesis, the complexity of generating these models
CONCLUSION have limited their use for studying HBV biology. [175] Overall,
studies aimed at enhancing our current understanding
Hepatocytes are the main target of an HBV infection, and of the HBV life cycle and identifying central factors
a chronic HBV infection is the major global cause for the involved in the development of HBV-associated HCC
development of HCC. [92,207] While the association between are still needed and remain critical for the generation
chronic HBV infections and HCC is well established, there of novel therapeutics to inhibit HBV replication and the
are still gaps in our understanding of how a chronic development of HBV-associated HCC.
HBV infection can lead to HCC development. The high
worldwide prevalence of chronic HBV infections, the Financial support and sponsorship
limited therapeutic options currently available for the The work was partially supported by an NIH predoctoral
treatment of chronic HBV infections, the increased global fellowship to RJL; the grant number is F31CA171712.
incidence of HCC, the high mortality rate of individuals
with HCC, and the close correlation between chronic Conflicts of interest
HBV infections and HCC development have generated There are no conflicts of interest.
considerable interest in understanding HBV biology and
elucidating the molecular mechanisms that underlie REFERENCES
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178 Hepatoma Research | Volume 2 | July 1, 2016