期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 33, 页码 12193-12198出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1412631111
关键词
HBV persistence; innate immunity; viral hepatitis
资金
- The Center for Basic and Translational Research on Disorders of the Digestive System
- Skolkovo Institute of Science and Technology [022423-003]
- National Institutes of Health [UH2 EB017103, DK085713, 1K08DK101754]
- Koch Institute Support Grant, National Cancer Institute (Swanson Biotechnology Center) [P30-CA14051]
- American Gastroenterology Association Research Scholar Award
- Fannie and John Hertz Foundation
- National Science Foundation
- National Center for Research Resources [8 UL1 TR000043]
- National Center for Advancing Translational Sciences, National Institutes of Health
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.
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