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Title: Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics

Abstract

Background: Chimeric uPA/SCID mice reconstituted with humanized livers are useful for studying 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 novel in vivo HBV infection model is lacking. Methods: 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 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. Results: During the first 6 h p.i. serum HBV declined in repopulated uPA/SCID mice with a t 1/2=62 min [95%CI=59-67min]. 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 h 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/ml. Serum HBV and intrahepatic HBV DNA were positively correlated (R2=0.98). Conclusions: HBV infection in uPA/SCID chimeric mice is highlymore » dynamic despite the absence of an adaptive immune response. The serum HBV t 1/2 in humanized uPA/SCID mice was estimated to be ~1 h regardless of inoculum size. Finally, 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 lifecycle and thus possibly reveal effective antiviral drug targets.« less

Authors:
 [1];  [2];  [3];  [3];  [4];  [5];  [1];  [6];  [7];  [4]; ORCiD logo [4];  [3]
  1. PhoenixBio Co., Ltd., Hiroshima (Japan); Hiroshima Univ., Hiroshima (Japan)
  2. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental & Theoretical Modeling, Division of Hepatology, Dept. of Medicine; Goethe Univ., Frankfurt (Germany). Inst. of Biostatistics and Mathematical Modeling
  3. Hiroshima Univ., Hiroshima (Japan)
  4. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental & Theoretical Modeling, Division of Hepatology, Dept. of Medicine
  5. PhoenixBio Co., Ltd., Hiroshima (Japan)
  6. Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental & Theoretical Modeling, Division of Hepatology, Dept. of Medicine; Univ. of Edinburgh, Scotland (United Kingdom). Centre for Immunity, Infection and Evolution
  7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Institutes of Health (NIH); PhoenixBio Co. Ltd.
OSTI Identifier:
1435513
Alternate Identifier(s):
OSTI ID: 1441016
Report Number(s):
LA-UR-15-27225
Journal ID: ISSN 0270-9139
Grant/Contract Number:  
AC52-06NA25396; R01-AI078881; R01- AI028433; R01-OD011095; R01-AI116868
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Hepatology
Additional Journal Information:
Journal Volume: 68; Journal Issue: 2; Journal ID: ISSN 0270-9139
Publisher:
American Association for the Study of Liver Diseases
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

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, and Chayama, Kazuaki. Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics. United States: N. p., 2018. Web. doi:10.1002/hep.29891.
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. Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics. United States. https://doi.org/10.1002/hep.29891
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, and Chayama, Kazuaki. Fri . "Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics". United States. https://doi.org/10.1002/hep.29891. https://www.osti.gov/servlets/purl/1435513.
@article{osti_1435513,
title = {Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics},
author = {Ishida, Yuji and Chung, Tje Lin and Imamura, Michio and Hiraga, Nobuhiko and Sen, Suranjana and Yokomichi, Hiroshi and Tateno, Chise and Canini, Laetitia and Perelson, Alan S. and Uprichard, Susan L. and Dahari, Harel and Chayama, Kazuaki},
abstractNote = {Background: Chimeric uPA/SCID mice reconstituted with humanized livers are useful for studying 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 novel in vivo HBV infection model is lacking. Methods: 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 cccDNA, and HBV RNA was measured in a subset of mice at 2, 4, 6, 10, and 13 weeks p.i. HBV half-life (t1/2) was estimated using a linear mixed-effects model. Results: During the first 6 h p.i. serum HBV declined in repopulated uPA/SCID mice with a t1/2=62 min [95%CI=59-67min]. Thereafter, viral decline slowed followed by a 2 day lower plateau. Subsequent viral amplification was multiphasic with an initial mean doubling time of t2= 8±3 h followed by an interim plateau before prolonged amplification (t2=2±0.5 days) to a final HBV steady state of 9.3 ± 0.3 log copies/ml. Serum HBV and intrahepatic HBV DNA were positively correlated (R2=0.98). Conclusions: HBV infection in uPA/SCID chimeric mice is highly dynamic despite the absence of an adaptive immune response. The serum HBV t1/2 in humanized uPA/SCID mice was estimated to be ~1 h regardless of inoculum size. Finally, 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 lifecycle and thus possibly reveal effective antiviral drug targets.},
doi = {10.1002/hep.29891},
url = {https://www.osti.gov/biblio/1435513}, journal = {Hepatology},
issn = {0270-9139},
number = 2,
volume = 68,
place = {United States},
year = {2018},
month = {3}
}

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Works referenced in this record:

Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees
journal, January 2004


Mouse models of hepatitis B and delta virus infection
journal, August 2014


Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection
journal, May 1997


Dynamics of hepatitis B virus clearance in chimpanzees
journal, November 2005


GH enhances proliferation of human hepatocytes grafted into immunodeficient mice with damaged liver
journal, September 2007


Expansion and contraction of the hepatitis B virus transcriptional template in infected chimpanzees
journal, February 2004


Near Completely Humanized Liver in Mice Shows Human-Type Metabolic Responses to Drugs
journal, September 2004


Acute Hepatitis B Virus Infection: Relation of Age to the Clinical Expression of Disease and Subsequent Development of the Carrier State
journal, April 1985


Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens
journal, October 2006


Cytokine-Sensitive Replication of Hepatitis B Virus in Immortalized Mouse Hepatocyte Cultures
journal, June 2002


Hepatitis B virus clearance rate estimates
journal, February 2009


Infection of human hepatocyte chimeric mouse with genetically engineered hepatitis B virus
journal, November 2005


Living in the liver: hepatic infections
journal, February 2012


Simultaneous detection of hepatitis C virus and interferon stimulated gene expression in infected human liver
journal, April 2014


Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life
journal, February 2013


Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection
journal, June 2003


Dissociation of HIV-1 from follicular dendritic cells during HAART: Mathematical analysis
journal, December 1999


Kinetics of Acute Hepatitis B Virus Infection in Humans
journal, April 2001


Hepatitis B Virus Infection
journal, December 1997


Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia
journal, August 2008


Stealth and Cunning: Hepatitis B and Hepatitis C Viruses
journal, July 2005


Modeling the mechanisms of acute hepatitis B virus infection
journal, July 2007


Hepatitis B Virus Immunopathogenesis
journal, April 1995


Immunobiology and Pathogenesis of Viral Hepatitis
journal, February 2006


Clinical presentation of acute viral hepatitis
journal, January 1990


The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection
journal, July 2009


Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs
journal, January 2005


Inferring Viral Dynamics in Chronically HCV Infected Patients from the Spatial Distribution of Infected Hepatocytes
journal, November 2014


CD8+ T Cells Mediate Viral Clearance and Disease Pathogenesis during Acute Hepatitis B Virus Infection
journal, January 2003


Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
journal, April 1987


Nucleic Acid Testing to Detect HBV Infection in Blood Donors
journal, January 2011


Use of Laser Capture Microdissection to Map Hepatitis C Virus–Positive Hepatocytes in Human Liver
journal, December 2013


Quantitation of Hepatitis B Virus Genomic DNA by Real-Time Detection PCR
journal, January 1999


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