Understanding hepatitis B virus dynamics and the antiviral effect of interferon-α treatment in humanized chimeric mice
Vladimir Reinharz 1 , Yuji Ishida 2 3 , Masataka Tsuge 2 4 5 , Karina Durso-Cain 4 6 , Tje Lin Chung 4 7 , Chise Tateno 2 3 , Alan S Perelson 8 , Susan L Uprichard 4 6 , Kazuaki Chayama 9 10 11 , Harel Dahari 12
Affiliations
Affiliations
1
Department of Computer Science, Université du Québec à Montréal, Montreal, Quebec, Canada.
2
Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.
3
PhoenixBio Co., Ltd., Hiroshima, Japan.
4
The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.
5
Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
6
Department of Microbiology and Immunology and Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois, USA.
7
Institut für Biostatistik and Mathematische Modellierung, Fachbereich Medizin, Goethe Universität, Frankfurt, Germany.
8
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
9
Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan [email protected][email protected].
10
Institute of Physical and Chemical Research (RIKEN) Center for Integrative Medical Sciences, Yokohama, Japan.
11
Collaborative Research Laboratory of Medical Innovation, Hiroshima University, Hiroshima, Japan.
12
The Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA [email protected][email protected].
PMID: 33910953 DOI: 10.1128/JVI.00492-20
Abstract
Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon-α are less completely defined. To advance our understanding, we mathematically modelled HBV kinetics during 14-day pegylated interferon-α-2a (pegIFN), LAM or pegIFN+LAM treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive-immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the 1st phase represents inhibition of intracellular HBV DNA synthesis and secretion which was similar under all treatments with overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the 2nd phase which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis with the steepest decline observed during pegIFN + LAM (1.28/d) and the slowest (0.1/d) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of adaptive immune response. Interestingly, combination treatment does not increase the initial inhibition of HBV production, but rather enhanced 2nd phase decline providing insight into the dynamics of HBV treatment response and the mode of action of interferon-α against HBV.ImportanceChronic hepatitis B virus (HBV) infection remains a global health care problem as we lack sufficient curative treatment options. Elucidating the dynamics of HBV infection and treatment response at the molecular level could facilitate the development of novel, more effective HBV antivirals. Currently, the only well-established small animal HBV infection model available is the chimeric uPA/SCID mice with humanized livers; however, the HBV inhibition kinetics under pegylated interferon-α (pegIFN) in this model system have not been determined in sufficient detail. In this study, viral kinetics in 39 humanized mice treated with pegIFN and/or lamivudine were monitored and analyzed using a mathematical-modelling approach. We found that the main mode of action of interferon-α is blocking HBV DNA synthesis and that the majority of synthesized HBV DNA is secreted. Our study provides novel insights into HBV DNA dynamics within infected human hepatocytes.