Understanding Hepatitis B Virus Dynamics and the Antiviral Effect of Interferon Alpha Treatment in Humanized Chimeric Mice
Vladimir Reinharz, Yuji Ishida, Masataka Tsuge, Karina Durso-Cain, Tje Lin Chung, Chise Tateno, Alan S. Perelson, Susan L. Uprichard, Kazuaki Chayama, Harel Dahari
Abstract
Chronic 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 IFN-α-2a (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 modeling approach. We found that the main mode of action of IFN-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.