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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1412631111

Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems.

Publication TypeJournal Article
Year of Publication2014
AuthorsShlomai, A, Schwartz, RE, Ramanan, V, Bhatta, A, de Jong, YP, Bhatia, SN, Rice, CM
JournalProc Natl Acad Sci U S A
Date Published2014 Aug 19
KeywordsAntiviral Agents, Cell Differentiation, Hepatitis B virus, Hepatocytes, Host-Pathogen Interactions, Humans, Induced Pluripotent Stem Cells, Models, Biological

Hepatitis B virus (HBV) chronically infects 400 million people worldwide and is a leading driver of end-stage liver disease and liver cancer. Research into the biology and treatment of HBV requires an in vitro cell-culture system that supports the infection of human hepatocytes, and accurately recapitulates virus-host interactions. Here, we report that micropatterned cocultures of primary human hepatocytes with stromal cells (MPCCs) reliably support productive HBV infection, and infection can be enhanced by blocking elements of the hepatocyte innate immune response associated with the induction of IFN-stimulated genes. MPCCs maintain prolonged, productive infection and represent a facile platform for studying virus-host interactions and for developing antiviral interventions. Hepatocytes obtained from different human donors vary dramatically in their permissiveness to HBV infection, suggesting that factors--such as divergence in genetic susceptibility to infection--may influence infection in vitro. To establish a complementary, renewable system on an isogenic background in which candidate genetics can be interrogated, we show that inducible pluripotent stem cells differentiated into hepatocyte-like cells (iHeps) support HBV infection that can also be enhanced by blocking interferon-stimulated gene induction. Notably, the emergence of the capacity to support HBV transcriptional activity and initial permissiveness for infection are marked by distinct stages of iHep differentiation, suggesting that infection of iHeps can be used both to study HBV, and conversely to assess the degree of iHep differentiation. Our work demonstrates the utility of these infectious systems for studying HBV biology and the virus' interactions with host hepatocyte genetics and physiology.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25092305
PubMed Central IDPMC4143014
Grant ListUL1 TR000043 / TR / NCATS NIH HHS / United States
UH2 EB017103 / EB / NIBIB NIH HHS / United States
1K08DK101754 / DK / NIDDK NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 DK085713 / DK / NIDDK NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
8 UL1 TR000043 / TR / NCATS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DK085713 / DK / NIDDK NIH HHS / United States
UH3 EB017103 / EB / NIBIB NIH HHS / United States
K08 DK101754 / DK / NIDDK NIH HHS / United States
K08 DK090576 / DK / NIDDK NIH HHS / United States