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Proc Natl Acad Sci U S A. 2014 Aug 19;111(33):12193-8. doi: 10.1073/pnas.1412631111. Epub 2014 Aug 4.

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

Author information

1
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;
2
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;Department of Health Sciences and Technology.
3
Department of Health Sciences and Technology.
4
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065;Division of Gastroenterology and Hepatology, Department of Medicine, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY 10065; and.
5
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;Department of Health Sciences and Technology,Department of Electrical Engineering and Computer Science,Broad Institute of MIT and Harvard, Cambridge, MA 02139Koch Institute for Integrative Cancer Research, andHoward Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139; ricec@rockefeller.edu sbhatia@mit.edu.
6
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065; ricec@rockefeller.edu sbhatia@mit.edu.

Abstract

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.

KEYWORDS:

HBV persistence; innate immunity; viral hepatitis

PMID:
25092305
PMCID:
PMC4143014
DOI:
10.1073/pnas.1412631111
[Indexed for MEDLINE]
Free PMC Article

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