Acute HBV 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

Acute HBV infection in humanized chimeric mice has multiphasic viral kinetics

Journal Article · Fri Mar 23 00:00:00 EDT 2018 · Hepatology

DOI:https://doi.org/10.1002/hep.29891· OSTI ID:1435513

Ishida, Yuji ^[1]; Chung, Tje Lin ^[2]; Imamura, Michio ^[3]; Hiraga, Nobuhiko ^[3]; Sen, Suranjana ^[4]; Yokomichi, Hiroshi ^[5]; Tateno, Chise ^[1]; Canini, Laetitia ^[6]; Perelson, Alan S. ^[7]; Uprichard, Susan L. ^[4]; ^[4]; Chayama, Kazuaki ^[3]

PhoenixBio Co., Ltd., Hiroshima (Japan); Hiroshima Univ., Hiroshima (Japan)
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
Hiroshima Univ., Hiroshima (Japan)
Loyola Univ. Medical Center, Maywood, IL (United States). Program for Experimental & Theoretical Modeling, Division of Hepatology, Dept. of Medicine
PhoenixBio Co., Ltd., Hiroshima (Japan)
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
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

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 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 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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL)

Sponsoring Organization:: National Institutes of Health (NIH); PhoenixBio Co. Ltd.; USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1435513

Alternate ID(s):: OSTI ID: 1441016

Report Number(s):: LA-UR-15-27225

Journal Information:: Hepatology, Journal Name: Hepatology Journal Issue: 2 Vol. 68; ISSN 0270-9139

Publisher:: American Association for the Study of Liver DiseasesCopyright Statement

Country of Publication:: United States

Language:: English

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