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

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:
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
Type:
Accepted Manuscript
Journal Name:
Hepatology
Additional Journal Information:
Journal Name: Hepatology; Journal ID: ISSN 0270-9139
Publisher:
American Association for the Study of Liver Diseases
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH); PhoenixBio Co. Ltd.
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science
OSTI Identifier:
1435513
Alternate Identifier(s):
OSTI ID: 1441016

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., 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. 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, and Chayama, Kazuaki. 2018. "Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics". United States. doi:10.1002/hep.29891.
@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},
journal = {Hepatology},
number = ,
volume = ,
place = {United States},
year = {2018},
month = {3}
}