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 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 absencemore » 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:

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]; Dahari, Harel  ^[4];

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Chayama, Kazuaki ^[3]

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+ Show Author Affiliations

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:

Fri Mar 23 00:00:00 EDT 2018

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; DE‐AC52‐06NA25396

Resource Type:

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