Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems
Amir Shlomai,Robert E. Schwartz,Vyas Ramanan,Ankit Bhatta,Ype P. de Jong,Sangeeta N. Bhatia,Charles M. Rice +6 more
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TLDR
It is reported 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.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.read more
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Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways
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TL;DR: STING is reported as a new target of HBV to antagonize IFN induction and identify the viral polymerase responsible for the inhibitory effect, thus providing an additional molecular mechanism by which HBV evades the innate immunity.
References
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Journal ArticleDOI
Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus
Huan Yan,Guocai Zhong,Guangwei Xu,Wenhui He,Zhiyi Jing,Zhenchao Gao,Yi Huang,Yonghe Qi,Bo Peng,Haimin Wang,Liran Fu,Mei Song,Pan Chen,Wenqing Gao,Bijie Ren,Yinyan Sun,Tao Cai,Xiaofeng Feng,Jianhua Sui,Wenhui Li +19 more
TL;DR: It is shown that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver that is a functional receptor for HBV and HDV.
Journal ArticleDOI
Viral Clearance Without Destruction of Infected Cells During Acute HBV Infection
Luca G. Guidotti,Rosemary Rochford,Josan Chung,Max Shapiro,Robert H. Purcell,Francis V. Chisari +5 more
TL;DR: Results demonstrate that noncytopathic antiviral mechanisms contribute to viral clearance during acute viral hepatitis by purging HBV replicative intermediates from the cytoplasm and covalently closed circular viral DNA from the nucleus of infected cells.
Journal ArticleDOI
Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells.
Karim Si-Tayeb,Fallon K. Noto,Masato Nagaoka,Jixuan Li,Michele A. Battle,Christine Duris,Paula E. North,Stephen Dalton,Stephen A. Duncan +8 more
TL;DR: It is demonstrated that mouse iPS cells retain full potential for fetal liver development and a procedure is described that facilitates the efficient generation of highly differentiated human hepatocyte‐like cells fromiPS cells that display key liver functions and can integrate into the hepatic parenchyma in vivo.
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