Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics

Ishida, Yuji; Chung, Tje Lin; Imamura, Michio; Hiraga, Nobuhiko; Sen, Suranjana; Yokomichi, Hiroshi; Tateno, Chise; Canini, Laetitia; Perelson, Alan S.; Uprichard, Susan L.; Dahari, Harel; Chayama, Kazuaki

doi:10.1002/hep.29891

Cited by 37 publications

(75 citation statements)

References 46 publications

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“…[131][132][133] More importantly, the HBV infection of HLCM is representative of infection in the human liver in terms of susceptibility, the abundance of cccDNA, replication efficiency, virion stability in the systemic circulation, and response to antiviral therapy. 134,135 HLCM-derived human hepatocytes also have a substantial superiority over other in vitro tools such as NTCP-expressing HepG2 cells or HepaRG cells. They retain a comparable susceptibility to HBV to that of in vivo infection of HLCM, thus only requiring an inoculum containing physiological titers whereas the aforementioned cell lines require an approximately 1,000 times higher titer to achieve the infection.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

“…To this end, HLCM is advantageous as the abundance of cccDNA in the liver of HBV-infected HLCM is comparable to that of the liver of an HBV-infected patient. 134,139 Furthermore, the abundance of cccDNA heavily fluctuates during cell division. 140 Therefore, studies addressing the regulatory mechanisms of cccDNA should be conducted with tools with absent or a minimal degree of cell division.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

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Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

et al. 2020

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Advancement in both bioengineering and cell biology of the liver led to the establishment of the first-generation humanized liver chimeric mouse (HLCM) model in 2001. The HLCM system was initially developed to satisfy the necessity for a convenient and physiologically representative small animal model for studies of hepatitis B virus and hepatitis C virus infection. Over the last two decades, the HLCM system has substantially evolved in quality, production capacity, and utility, thereby growing its versatility beyond the study of viral hepatitis. Hence, it has been increasingly employed for a variety of applications including, but not limited to, the investigation of drug metabolism and pharmacokinetics and stem cell biology. To date, more than a dozen distinctive HLCM systems have been established, and each model system has similarities as well as unique characteristics, which are often perplexing for end-users. Thus, this review aims to summarize the history, evolution, advantages, and pitfalls of each model system with the goal of providing comprehensive information that is necessary for researchers to implement the ideal HLCM system for their purposes. Furthermore, this review article summarizes the contribution of HLCM and its derivatives to our mechanistic understanding of various human liver diseases, its potential for novel applications, and its current limitations.

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Section: Hepatitis B Virusmentioning

confidence: 99%

Section: Hepatitis B Virusmentioning

confidence: 99%

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

et al. 2020

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“…Thirty-nine uPA +/+ /SCID +/+ chimeric mice with humanized liver were produced as described previously (9)(10)(11). Three different commercially available frozen lots of human hepatocytes (2 year old Hispanic male, 2YM; 5 year old African American male, 5YM; 1 year old Caucasian female, 1YF) were purchased from BD Biosciences Discovery Labware, San Jose, CA, USA (2YM and 5YM) and In Vitro Technologies, Baltimore, MD, USA (1YF).…”

Section: Production Of Upa/scid Chimeric Mice With Humanized Livermentioning

confidence: 99%

“…9740 IU) was intravenously injected into chimeric mice whose hAlb levels were 4.2-15.0 mg/mL by 7 to 11 weeks after human hepatocyte transplantation (corresponding to a replacement index of 53.7-89.3%). All 39 mice were reached high HBV steady state levels as described previously (11) .…”

Section: Infection Of Upa/scid Humanized Mice With Hbvmentioning

confidence: 99%

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Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

Canini

Ishida

Tsuge

et al. 2020

Preprint

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BackgroundWhereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during pegylated interferon-α-2a (pegIFN), LAM and pegIFN+LAM treatment of chronically HBV-infected humanized uPA/SCID chimeric mice.MethodsThirty-nine uPA/SCID mice with humanized livers whose pre-treatment steady-state serum HBV reached 9.2±0.4 logIU/mL were treated with pegIFN, LAM or pegIFN+LAM for 14 days. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a nonlinear mixed effect viral kinetic model and simultaneously fit it to the serum and intracellular HBV DNA data.ResultsUnexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Modeling predicts that the first phase represents pegIFN inhibiting intracellular HBV DNA synthesis with efficacy of 86%, which was similar under LAM and pegIFN+LAM. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN+LAM (0.46/d) and the slowest (0.052/d) during pegIFN mono-treatment.ConclusionsReminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production; however, enhancement of second phase decline is observed providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV.Author SummaryChronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamic of HBV infection and treatment at the molecular level would potentially facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV infection kinetics under interferon-α (IFN) in this model system have not been determined in sufficient detail to support the in-depth studies of HBV treatment response needed to identify/confirm more effective drug targets. In this study 39 chronic HBV-infected uPA/SCID humanized mice treated with IFN and/or lamivudine were analysed using a mathematical modelling approach. We found that IFN main mode of action is blocking HBV DNA synthesis and that 73% of synthesized HBV DNA per are secreted from infected cells. Our data-driven mathematical modeling study provides novel insights into IFN anti-HBV mechanism(s) and viral-host interplay at the molecular level.

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Hepatitis B virus‐specific human stem cell memory T cells differentiate into cytotoxic T cells and eradicate HBV‐infected hepatocytes in mice

Abe‐Chayama,

Kawase,

Ichinohe

et al. 2024

FEBS Letters

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Chronic infection with the hepatitis B virus (HBV) induces progressive hepatic impairment. Achieving complete eradication of the virus remains a formidable challenge. Cytotoxic T lymphocytes, specific to viral antigens, either exhibit a numerical deficiency or succumb to an exhausted state in individuals chronically afflicted with HBV. The comprehension of the genesis and dissemination of stem cell memory T cells (TSCMs) targeting HBV remains inadequately elucidated. We identified TSCMs in subjects with chronic HBV infection and scrutinized their efficacy in a murine model with human hepatocyte transplants, specifically the TK‐NOG mice. TSCMs were discerned in all subjects under examination. Introduction of TSCMs into the HBV mouse model precipitated a severe necro‐inflammatory response, resulting in the elimination of human hepatocytes. TSCMs may constitute a valuable tool in the pursuit of a remedial therapy for HBV infection.

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Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics

Cited by 37 publications

References 46 publications

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice

Hepatitis B virus‐specific human stem cell memory T cells differentiate into cytotoxic T cells and eradicate HBV‐infected hepatocytes in mice

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