Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

Bissig, Karl‐Dimiter; Wieland, Stefan; Tran, Phu Dac; Isogawa, Masanori; Le, Tam Thi; Chisari, Francis V.; Verma, Inder M.

doi:10.1172/jci40094

Cited by 314 publications

(327 citation statements)

References 25 publications

(32 reference statements)

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Section: Chimpanzee Model: Adaptive Immune Responsesmentioning

confidence: 99%

“…Despite its technical difficulties (e.g. transplantation of human hepatocytes), this model is permissive for HCV infection (Bissig et al, 2010;Mercer et al, 2001). Since it is immunodeficient, the host adaptive immune responses cannot be studied.…”

Section: Chimpanzee Model: Adaptive Immune Responsesmentioning

confidence: 99%

“…However, the main limitation of using this species is the lack of its genetic information because it is an outbred stock. In addition, the tree shrew's genome has not been completely sequenced, further limiting their potential for studying host immune responses (Bissig et al, 2010).The development of inbred HCV-permissive mice could solve the limitations of the tree shrew model, since a lot of information is available about the genetic characteristics as an inbred stock, the genome and the immune systems. The use of mice has also technical advantages, e.g.…”

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confidence: 99%

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Experimental models to study the immunobiology of hepatitis C virus

Lohmann

Bartenschlager

et al. 2010

Journal of General Virology

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Effective host immune responses are essential for the control of hepatitis C virus (HCV) infection and persistence of HCV has indeed been attributed to their failure. In recent years, several in vitro and in vivo experimental models have allowed studies of host immune responses against HCV. Numerous observations derived from these models have improved our understanding of the mechanisms responsible for the host's ability to clear the virus as well as of the mechanisms responsible for the host's failure to control HCV replication. Importantly, several findings obtained with these model systems have been confirmed in studies of acutely or chronically HCV-infected individuals. Collectively, several mechanisms are used by HCV to escape host immune responses, such as poor induction of the innate immune response and escaping/impairing adaptive immunity. In this review, we summarize current findings from experimental models available for studies of the immune response targeting HCV and discuss the relevance of these findings for the in vivo situation in HCV-infected humans. IntroductionHepatitis C virus (HCV) is an enveloped RNA virus that belongs to the genus Hepacivirus within the family Flaviviridae. The positive-strand genome has a length of 9.6 kb and it encodes a polyprotein that is cleaved by viral and cellular proteases into 10 different proteins (reviewed by Moradpour et al., 2007). The structural proteins core, envelope protein 1 (E1) and E2 reside in the amino-terminal region of the polyprotein and they are the main constituents of infectious virus particles. The hydrophobic p7 protein together with non-structural protein 2 (NS2) are required for virion assembly. The serine-type protease residing in NS3 forms a stable complex with the NS4A cofactor and contributes to polyprotein cleavage. NS4B induces alterations of intracellular membranes, designated the membranous web, which is thought to be the site of viral RNA replication. NS5A is required for RNA replication and assembly and NS5B is the RNA-dependent RNA polymerase.HCV has a narrow host range and infects only humans and chimpanzees. It is estimated that~130 million people are persistently infected by HCV worldwide (reviewed by Shepard et al., 2005). Limited therapy options and the lack of a preventive vaccine aggravate this medical issue (reviewed by Lauer & Walker, 2001). Of note, the virus is able to establish persistence in approximately two-thirds of infected subjects and has thus become a major cause of chronic liver inflammation that can culminate in liver cirrhosis or even hepatocellular carcinoma (reviewed by Lauer & Walker, 2001). It is still not completely clear why successful immune responses allow only one-third of infected subjects to clear HCV. A major limitation when addressing this issue is the lack of an immunocompetent small animal model. Importantly, however, by using novel cell culture systems, some of these hurdles have now been overcome and first important insights into the intimate interaction between HCV and its host cell have b...

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Section: Chimpanzee Model: Adaptive Immune Responsesmentioning

confidence: 99%

Section: Chimpanzee Model: Adaptive Immune Responsesmentioning

confidence: 99%

mentioning

confidence: 99%

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Experimental models to study the immunobiology of hepatitis C virus

Lohmann

Bartenschlager

et al. 2010

Journal of General Virology

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“…Elsewhere, humanized mice, based on genetic manipulation or transplantation of human cells, have also been highly enabling (5). Mice with chimeric livers show encouraging drug responsiveness (6,7) and pathogen susceptibility (8)(9)(10)(11)(12). However, these models are confined to liver-injury, immunodeficient recipients and depend on the coordinated injection of high-quality human hepatocytes, which must home to the liver from the injection site, engraft, and expand over weeks to months within the injured host (13,14).…”

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confidence: 99%

Humanized mice with ectopic artificial liver tissues

Chen

Thomas

Ong

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

144

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"Humanized" mice offer a window into aspects of human physiology that are otherwise inaccessible. The best available methods for liver humanization rely on cell transplantation into immunodeficient mice with liver injury but these methods have not gained widespread use due to the duration and variability of hepatocyte repopulation. In light of the significant progress that has been achieved in clinical cell transplantation through tissue engineering, we sought to develop a humanized mouse model based on the facile and ectopic implantation of a tissue-engineered human liver. These human ectopic artificial livers (HEALs) stabilize the function of cryopreserved primary human hepatocytes through juxtacrine and paracrine signals in polymeric scaffolds. In contrast to current methods, HEALs can be efficiently established in immunocompetent mice with normal liver function. Mice transplanted with HEALs exhibit humanized liver functions persistent for weeks, including synthesis of human proteins, human drug metabolism, drug-drug interaction, and drug-induced liver injury. Here, mice with HEALs are used to predict the disproportionate metabolism and toxicity of "major" human metabolites using multiple routes of administration and monitoring. These advances may enable manufacturing of reproducible in vivo models for diverse drug development and research applications.P reclinical models provide a critical window into human physiology and are important for determining drug safety and efficacy. Bioengineering advances have produced in vivo platforms with improved disease modeling (1, 2), absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) (3, 4), and circulation-mimicking capabilities (4). "Human-on-a-chip" systems, however, show limited recapitulation of pharmacokinetics and cannot support clinically relevant administration routes. Elsewhere, humanized mice, based on genetic manipulation or transplantation of human cells, have also been highly enabling (5). Mice with chimeric livers show encouraging drug responsiveness (6, 7) and pathogen susceptibility (8-12). However, these models are confined to liver-injury, immunodeficient recipients and depend on the coordinated injection of high-quality human hepatocytes, which must home to the liver from the injection site, engraft, and expand over weeks to months within the injured host (13,14). Given the limitations of current preclinical models, human metabolites and their downstream effects often go undetected until clinical trials, the most costly and dangerous phase of drug development (15).Here we develop an improved humanized mouse model by implantation of tissue-engineered human ectopic artificial livers (HEALs). In the field of tissue engineering, polymeric scaffolds are widely used for cell and drug delivery in vivo (16,17). Primary hepatocytes, however, are challenging to maintain and implant via biomaterials due to their unstable phenotype, variable engraftment efficiencies, and high metabolic needs (18). Use of partial hepatectomy with portal-caval ...

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“…Ces différents critères semblent désormais réunis dans un modèle qui vient d'être publié dans la revue Gastroenterology [7]. L'animal receveur est une souris transgénique exprimant dans ses hépatocy-tes une caspase 8 dimérisable et donc L'infection de cette souris immunodé-primée par le VHC n'a été que récemment démontrée [6]. En revanche, l'absence d'un système immunitaire humain fonctionnel ne permet d'induire une fibrose hépatique dans aucun de ces modèles.…”

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Des souris humanisées pour l’étude du virus de l’hépatite C

Gilgenkrantz

2011

Med Sci (Paris)

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Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment

Cited by 314 publications

References 25 publications

Experimental models to study the immunobiology of hepatitis C virus

Experimental models to study the immunobiology of hepatitis C virus

Humanized mice with ectopic artificial liver tissues

Des souris humanisées pour l’étude du virus de l’hépatite C

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