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Cited by 47Hepatitis B Virus StudiesHepatitis C virus researchLiver physiology and pathology

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

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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·2018·Hepatology
DOI 10.1002/hep.29891PMC PMC6097938
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Abstract

Chimeric urokinase type plasminogen activator (uPA)/severely severe combined immunodeficiency (SCID) mice reconstituted with humanized livers are useful for studying hepatitis B virus (HBV) infection in the absence of an adaptive immune response. However, the detailed characterization of HBV infection kinetics necessary to enable in‐depth mechanistic studies in this in vivo HBV infection model is lacking. To characterize HBV kinetics post‐inoculation (p.i.) to steady state, 42 mice were inoculated with HBV. Serum HBV DNA was frequently measured from 1 minute to 63 days p.i. Total intrahepatic HBV DNA, HBV covalently closed circular DNA (cccDNA), and HBV RNA was measured in a subset of mice at 2, 4, 6, 10, and 13 weeks p.i. HBV half‐life (t 1/2 ) was estimated using a linear mixed‐effects model. During the first 6 hours p.i., serum HBV declined in repopulated uPA/SCID mice with a t 1/2 = 62 minutes (95% confidence interval [CI] = 59‐67). Thereafter, viral decline slowed followed by a 2‐day lower plateau. Subsequent viral amplification was multiphasic with an initial mean doubling time of t 2 = 8 ± 3 hours followed by an interim plateau before prolonged amplification (t 2 = 2 ± 0.5 days) to a final HBV steady state of 9.3 ± 0.3 log copies (cps)/mL. Serum HBV and intrahepatic HBV DNA were positively correlated (R 2 = 0.98). Conclusion: HBV infection in uPA/SCID chimeric mice is highly dynamic despite the absence of an adaptive immune response. Serum HBV t 1/2 in humanized uPA/SCID mice was estimated to be ∼1 hour regardless of inoculum size. The HBV acute infection kinetics presented here is an important step in characterizing this experimental model system so that it can be effectively used to elucidate the dynamics of the HBV life cycle and thus possibly reveal effective antiviral drug targets. (H epatology 2018).

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  • Humanized mice have already shown promise in modelling chronic liver diseases like MASLD and human liver viral infections.

    “Such humanized mice have already shown promise in modelling of chronic liver diseases like MASLD(56) and human liver viral infections(57).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [57]

  • Mice exposed to ethanol exhibit an imbalance between the naive and memory compartments of their CD4+ T cells due to increased homeostatic proliferation of memory cells.

    “while mice exposed to ethanol exhibit an imbalance between the naive and memory compartments of their CD4+ T cells due to increased homeostatic proliferation of memory cells (56, 57).”

    From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [57]

    The Materials and Methods (Mice) describes humanized-liver mice inoculated with HBV, and the Results reports viral measurements. Searches for ethanol exposure and naive or memory CD4+ T-cell proliferation found no passage addressing the claim. (LLM, conf=0.76)

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Metadata

Authors
Ishida, Y., Chung, T. L., Imamura, M., Hiraga, N., Sen, S., Yokomichi, H., Tateno, C., Canini, L., Perelson, A. S., Uprichard, S. L., Dahari, H., & Chayama, K.
Affiliations
  • Hiroshima University (JP)
  • Goethe University Frankfurt (DE)
  • Loyola University Medical Center (US)
  • PhoenixBio (Japan) (JP)
  • The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine,Loyola University Medical Center,Maywood,IL
  • Los Alamos National Laboratory (US)
Corresponding author
  • Dahari, Harel
  • Chayama, Kazuaki
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-06-06
Volume
68
Issue
2
Pages
473-484
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.29891
PMC
PMC6097938
OpenAlex
W2791377220
Cited by
47
References
0
Citations by year
2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 3
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • U.S. Department of Energy (DE-AC52-06NA2-5396, AC52-06NA25396, contract DE-AC52-06NA25396)
  • Japan Agency for Medical Research and Development (17fk0210104h0001)
  • National Institutes of Health (DE-AC52-06NA25396, R01OD011095, AI028433, AI078881)
  • Japan Society for the Promotion of Science (17K09427)
  • National Institute of Allergy and Infectious Diseases (R01AI028433, R01AI116868, R01AI078881)
Topics
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
  • Health Sciences › Medicine › Hepatology › Hepatitis C virus research
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
hepatitis B virus, acute hepatitis B, viral dynamics, humanized liver, viral amplification, covalently closed circular DNA, HBV RNA, HBV life cycle, antiviral drug targets
MeSH terms
Animals, Chimera, Disease Models, Animal, DNA, Viral, Female, Hepatitis B, Hepatitis B virus, Humans, Male, Urokinase-Type Plasminogen Activator, Virus Replication, Mice, SCID, Hepatocytes, Mice

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