Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Hu, Jianming; Lin, You Yu; Chen, Pei‐Jer; Watashi, Koichi; Wakita, Takaji

doi:10.1053/j.gastro.2018.06.093

Cited by 91 publications

(81 citation statements)

References 178 publications

(156 reference statements)

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“…These models can simulate the natural history of HBV infection in vivo, as well as the innate and adaptive immune responses against HBV. Therefore, they have been widely used in HBV‐related research . In our recent work, a dual humanized chimeric mouse model was established that could replicate the entire viral life cycle, persistent viraemia, and immune responses of HBV infection in human .…”

Section: Potential Animal Models For Coexisting Chb and Nafldmentioning

confidence: 99%

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

Zhang

Lin

Jiang

et al. 2020

Liver International

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Despite the widespread use of vaccines and antiviral drugs, approximately 350‐400 million patients with chronic hepatitis B (CHB) remain worldwide, who carry high risk of cirrhosis and liver carcinoma. Moreover, owing to improvements in global living standards and lifestyle changes, non‐alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. Coexistence of NAFLD and CHB is commonly observed, especially in Asian CHB populations; however, little is known regarding the relationship between these two diseases as comorbidities. In this review, we summarize recent advances in clinical and basic researches related to the underlying mutual interactions, as well as potential animal models to facilitate further investigation.

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Section: Potential Animal Models For Coexisting Chb and Nafldmentioning

confidence: 99%

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

Zhang

Lin

Jiang

et al. 2020

Liver International

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“…We tested the effects of ATR-CHK1 inhibitors on HBV CCC DNA formation during HBV infection of primary human hepatocytes (PHHs), which is thought to mimic best the authentic host cells of HBV infection, i.e., hepatocytes in the human liver (40). Again, the results showed that multiple inhibitors of the ATR-CHK1 pathway could decrease HBV CCC DNA formation in PHHs during HBV infection ( Fig.…”

Section: Inhibition Of the Atr-chk1 Pathway Suppressed Hbv CCC Dna Fomentioning

confidence: 99%

Involvement of Host ATR-CHK1 Pathway in Hepatitis B Virus Covalently Closed Circular DNA Formation

Luo

Luckenbaugh

et al. 2020

mBio

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The covalently closed circular (CCC) DNA of hepatitis B virus (HBV) functions as the only viral transcriptional template capable of producing all viral RNA species and is essential to initiate and sustain viral replication. CCC DNA is converted from a relaxed circular (RC) DNA, in which neither of the two DNA strands is covalently closed. As RC DNA mimics damaged cellular DNA, the host cell DNA damage repair (DDR) system is thought to be responsible for HBV CCC DNA formation. The potential role of two major cellular DDR pathways, the ataxia telangiectasia mutated (ATM) pathway and the ATM and Rad3-related (ATR) pathway, in HBV CCC DNA formation was thus investigated. Inhibition, or expression knockdown, of ATR and its downstream signaling factor CHK1, but not of ATM, decreased CCC DNA formation during de novo HBV infection, as well as intracellular CCC DNA amplification, when RC DNA from extracellular virions and intracellular nucleocapsids, respectively, is converted to CCC DNA. Furthermore, a novel RC DNA processing product with 5′ truncated minus strands was detected when the ATR-CHK1 pathway was inhibited, further indicating that this pathway controls RC DNA processing during its conversion to CCC DNA. These results provide new insights into how host cells recognize and process HBV RC DNA in order to produce CCC DNA and have implications for potential means to block CCC DNA production. IMPORTANCE Hepatitis B virus (HBV) chronically infects hundreds of millions of people and remains a major cause of viral hepatitis, cirrhosis, and liver cancer. HBV persistence is sustained by a viral nuclear episome that directs all viral gene expression needed to support viral replication. The episome is converted from an incomplete DNA precursor in viral particles in an ill-understood process. We report here that the incomplete DNA precursor is recognized by the host cell in a way similar to the sensing of damaged cellular DNA for subsequent repair to form the nuclear episome. Intense efforts are ongoing to develop novel antiviral strategies to eliminate CCC DNA so as to cure chronic HBV infection. Our results here provide novel insights into, and suggest novel ways of perturbing, the process of episome formation. Furthermore, our results inform mechanisms of cellular DNA damage recognition and repair, processes essential for normal cell growth.

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“…1B-D). To confirm this result, we established a strain of HepG2 cells engineered to express the human solute carrier family 10 member 1 ( SLC10A1 , also called NTCP) gene (HepG2-NTCP cells), which allows them susceptible to HBV infection (Hu et al , 2019). Targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) results showed a significant increase in UDP-GlcNAc and glucose levels in HBV-infected HepG2-NTCP, stable HBV-expressing HepAD38 (a tetracycline (Tet) inducible HBV expression cell line) (Fig.…”

Section: Resultsmentioning

confidence: 98%

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

Gao

Yang

et al. 2020

Preprint

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26Viruses hijack the host cell machinery to promote viral replication; however, the mechanism 27 by which metabolic reprogramming regulates innate antiviral immunity in the host remains 28 elusive. Herein, we found that Hepatitis B virus (HBV) infection upregulates glucose 29 transporter 1expression, promotes hexosamine biosynthesis pathway (HBP) activity, and 30 enhances O-linked β-N-acetylglucosamine (O-GlcNAc) modification of downstream proteins. 31 HBP-mediated O-GlcNAcylation positively regulates host antiviral response against HBV in 32 vitro and in vivo. Mechanistically, O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation 33 of sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) on 34 Ser93 stabilizes SAMHD1 and enhances its antiviral activity. In addition, O-GlcNAcylation of 35 SAMHD1 promoted its antiviral activity against human immunodeficiency virus-1 in vitro. In 36 conclusion, the results of our study reveal a link between HBP, O-GlcNAc modification, and 37 innate antiviral immunity by targeting SAMHD1. Therefore, the results of this study 38 demonstrate a strategy for the potential treatment of HBV infection by modulating HBP 39 activity. 40 41 Keywords: Hepatitis B virus / O-linked β-N-acetylglucosamine modification / sterile alpha 42 motif and histidine/aspartic acid domain-containing protein 1 / antiviral immunity 43 /Hexosamine biosynthetic pathway 44 2 45Immunometabolism is an emerging field that highlights the importance of specific metabolic 46 pathways in immune regulation. Metabolic enzymes, such as glyceraldehyde 3-phosphate 47 dehydrogenase and pyruvate kinase isozyme M2 can directly modulate immune cell 48 activation (Chang et al, 2013; Palsson-McDermott et al, 2015). In addition to providing 49 energy and building blocks for biosynthesis, metabolites have been shown to participate in 50 epigenetic modification and signaling transduction. the glycolytic product lactate not only 51 regulates gene expression by histone acetylation (Zhang et al, 2019a), but also acts as a 52 suppressor of type I interferon signaling by interacting with the mitochondrial antiviral 53 signaling protein MAVS (Zhang et al, 2019b). Itaconate-another important metabolite for 54 immune function-downregulates type I interferon signaling during viral infection by 55 promoting alkylation of Kelch-like ECH-associated protein 1 and activation of 56 anti-inflammatory proteins, including nuclear factor erythroid 2-related factor 2 (Mills et al, 57 2018, 1; O'Neill & Artyomov, 2019).58 59 Viruses are obligate parasites that rely on the biosynthetic machinery of the host to complete 60 their life cycle. They hijack the host cell machinery upon entry to fulfill their energetic and 61 biosynthetic demands for viral replication. Human cytomegalovirus (HCMV) and herpes 62 simplex virus-1 (HSV-1) remodel host cells to perform distinct, virus-specific metabolic 63 programs (Vastag et al, 2011). HCMV reprograms host metabolism by upregulating the 64 expression of carbohydrate-response element bind...

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Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Cited by 91 publications

References 178 publications

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

Chronic hepatitis B and non‐alcoholic fatty liver disease: Conspirators or competitors?

Involvement of Host ATR-CHK1 Pathway in Hepatitis B Virus Covalently Closed Circular DNA Formation

O-GlcNAcylation of SAMHD1 Indicating a Link between Metabolic Reprogramming and Anti-HBV Immunity

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