Modeling hepatitis B virus infection, immunopathology and therapy in mice

Liu, Cheng; Li, Feng; Bility, Moses T.; Murphy, Christopher M.; Su, Lishan

doi:10.1016/j.antiviral.2015.06.012

Cited by 26 publications

(22 citation statements)

References 98 publications

(142 reference statements)

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“…To study hepatotropic pathogens, human liver chimeras have been developed [Figure 2 and reviewed in (73, 74)]. In all models, the common theme is destruction of murine hepatocytes to permit space for engraftment of human hepatocytes.…”

Section: Human-murine Liver Chimeric Mouse Models For Infectious Diseasementioning

confidence: 99%

Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

442

384

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Immunodeficient mice engrafted with functional human cells and tissues, i.e., “humanized mice”, have become increasingly important as small pre-clinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000’s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft versus host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly “personalized” medicine in the clinic. This review discusses recent progress in the development and use of humanized mice, and highlights their utility for the study of human diseases.

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Section: Human-murine Liver Chimeric Mouse Models For Infectious Diseasementioning

confidence: 99%

Humanized Mouse Models of Clinical Disease

Walsh

Kenney

Jangalwe

et al. 2017

Annu. Rev. Pathol. Mech. Dis.

442

384

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“…[156] Unfortunately, a relatively low HBV infection efficiency and lack of genetically uniform tree shrew strains has limited their use. [157] …”

Section: Model Systems Used In the Study Of Hbvmentioning

confidence: 99%

“…[157, 172] Typically these models can be separated into two categories: HBV-/HBx-tg mice, which constitutively express HBV or HBx, respectively, and mice that are delivered the HBV genome or an HBx-expressing plasmid by hydrodynamic tail-vein injection. Although mouse hepatocytes cannot be directly infected with HBV, the use of tail-vein-delivered DNA or HBV-tg mice allows studies of the impact of HBV replication on hepatocyte physiology; HBx-tg mice similarly aid in the study of HBx-mediated effects.…”

Section: Model Systems Used In the Study Of Hbvmentioning

confidence: 99%

Hepatitis B virus molecular biology and pathogenesis

Lamontagne¹,

Bagga²,

Bouchard³

2016

145

109

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As obligate intracellular parasites, viruses need a host cell to provide a milieu favorable to viral replication. Consequently, viruses often adopt mechanisms to subvert host cellular signaling processes. While beneficial for the viral replication cycle, virus-induced deregulation of host cellular signaling processes can be detrimental to host cell physiology and can lead to virus-associated pathogenesis, including, for oncogenic viruses, cell transformation and cancer progression. Included among these oncogenic viruses is the hepatitis B virus (HBV). Despite the availability of an HBV vaccine, 350–500 million people worldwide are chronically infected with HBV, and a significant number of these chronically infected individuals will develop hepatocellular carcinoma (HCC). Epidemiological studies indicate that chronic infection with HBV is the leading risk factor for the development of HCC. Globally, HCC is the second highest cause of cancer-associated deaths, underscoring the need for understanding mechanisms that regulate HBV replication and the development of HBV-associated HCC. HBV is the prototype member of the Hepadnaviridae family; members of this family of viruses have a narrow host range and predominately infect hepatocytes in their respective hosts. The extremely small and compact hepadnaviral genome, the unique arrangement of open reading frames, and a replication strategy utilizing reverse transcription of an RNA intermediate to generate the DNA genome are distinguishing features of the Hepadnaviridae. In this review, we provide a comprehensive description of HBV biology, summarize the model systems used for studying HBV infections, and highlight potential mechanisms that link a chronic HBV-infection to the development of HCC. For example, the HBV X protein (HBx), a key regulatory HBV protein that is important for HBV replication, is thought to play a cofactor role in the development of HBV-induced HCC, and we highlight the functions of HBx that may contribute to the development of HBV-associated HCC.

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“…Current treatments for chronic HBV infection have been discussed in other issues of this compendium (Block et al, 2015; Chang and Guo, 2015; Cheng et al, 2015; Gish et al, 2015a; Gish et al, 2015b; Tavis and Lomonosova, 2015; Yan et al, 2015; Zlotnick et al, 2015). They include interferon and nucleoside RT inhibitors (NRTIs, also called nucleotide RT inhibitors if they are the phosphorylated form, such as tenofovir and adefovir) (De Clercq et al, 2010; Scaglione and Lok, 2012).…”

Section: Current Antivirals Target Hbv Dna Synthesismentioning

confidence: 99%

“…While the polymerase, with its many functions, has been successfully targeted by NRTIs, the advent of combination therapies which include non-NRTIs as well as inhibitors of other viral components should further increase the effectiveness of HBV drug therapy. There are many strategies and compounds in development which target HBV or its life cycle beyond the RT and are further discussed elsewhere in this symposium (Block et al, 2015; Chang and Guo, 2015; Cheng et al, 2015; Gish et al, 2015a; Gish et al, 2015b; Tavis and Lomonosova, 2015; Yan et al, 2015; Zlotnick et al, 2015). Assuming that new cccDNA formation is needed to sustain HBV persistence, combination therapies sufficiently potent to completely block rcDNA synthesis should be able to clear cccDNA and thus cure chronic HBV infection, once the preexisting cccDNA is removed by the host (Hu and Seeger, 2015).…”

Section: Potential For Developing Novel Rt Inhibitors In Combinationmentioning

confidence: 99%

Hepatitis B virus reverse transcriptase – Target of current antiviral therapy and future drug development

Clark

2015

Antiviral Research

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Hepatitis B virus (HBV) infections rely on the proper functioning of the viral polymerase enzyme, a specialized reverse transcriptase (RT) with multiple activities. All currently approved antiviral drugs for the treatment of chronic hepatitis B virus, except for interferon, target the RT and belong to the same chemical class - they are all nucleoside analogs. Viral DNA synthesis is carried out by the RT enzyme in several different steps, each with distinct RT conformational requirements. In principle, each stage may be targeted by distinct antiviral drugs. In particular, the HBV RT has the unique ability to initiate viral DNA synthesis using itself as a protein primer in a novel protein priming reaction. In order to help identify RT inhibitors and study their mechanisms of action, a number of experimental systems have been developed, each varying in its ability to dissect the protein priming and the subsequent stages of viral DNA synthesis reaction at the molecular level. Two of the most effective drugs to date, entecavir and tenofovir, can inhibit both the protein priming and the subsequent DNA elongation stages of HBV DNA synthesis. Interestingly, clevudine, a thymidine analog, can inhibit both protein priming and DNA elongation in a non-competitive manner and without being incorporated into the viral DNA. Thus, a nucleoside RT inhibitor (NRTI) can functionally mimic a non-NRTI (NNRTI) in its inhibition of the HBV RT. Therefore, novel NRTIs as well as NNRTIs may be developed to inhibit the DNA synthesis activity of the HBV RT. Furthermore, additional activities of the RT that are also essential to HBV replication, including specific recognition of the viral RNA and its packaging into viral nucleocapsids, may be exploited for antiviral development. To achieve a more potent inhibition of viral replication and ultimately cure chronic HBV infection, the next generation of anti-HBV therapies will likely need to include NRTIs, NNRTIs, and other agents that target the viral RT as well as other viral and host factors in various combinations. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B."

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Modeling hepatitis B virus infection, immunopathology and therapy in mice

Cited by 26 publications

References 98 publications

Humanized Mouse Models of Clinical Disease

Humanized Mouse Models of Clinical Disease

Hepatitis B virus molecular biology and pathogenesis

Hepatitis B virus reverse transcriptase – Target of current antiviral therapy and future drug development

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