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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01735

rt269I Type of Hepatitis B Virus (HBV) Leads to HBV e antigen negative infections and Liver Disease Progression via Mitochondrial Stress Mediated Type I Interferon Production in chronic patients with genotype C infections

 So-Young Lee1, Yu-Min Choi1,  Soo-Bin Yang1, JunHyeok Lee1, Won-Hyeok Choe2,  Yoon-Hoh Kook1 and  Bum-Joon Kim1*
  • 1Seoul National University College of Medicine, South Korea
  • 2Graduate School of Medicine, Konkuk University, South Korea

Hepatitis B virus infection is a serious global health problem and causes life-threatening liver disease. In particular, genotype C shows high prevalence and sever liver disease compared with other genotypes. However, the underlying mechanisms regarding virological traits still remain unclear. This study investigated the clinical factors and capacity to modulate Type I interferon (IFN-I) between two HBV polymerase polymorphisms rt269L and rt269I in genotype C. This report compared clinical factors between rt269L and rt269I in 220 Korean chronic patients with genotype C infections. The prevalence of preC mutations between rt269L and rt269I was compared using this study’s cohort and the GenBank database. For in vitro and in vivo experiments, transient transfection using HBV genome plasmid and HBV virion infection using HepG2-hNTCP-C4 and HepaRG systems and hydrodynamic injection of HBV genome into mice tail were conducted, respectively. This report’s clinical data indicated that rt269I versus rt269L was more related to HBV e antigen (HBeAg) negative serostatus, lower levels of HBV DNA and HBsAg, and disease progression. Our epidemiological study showed HBeAg negative infections of rt269I infections were attributed to a higher frequency of preC mutations at 1896 (G to A). Our in vitro and in vivo study also found that rt269I could lead to mitochondrial stress mediated STING dependent IFN-I production, resulting in decreasing HBV replication via the induction of heme-oxygenase-1. In addition, we also found that rt269I could lead to enhanced iNOS mediated NO production in an IFN-I dependent manner. These data demonstrated that rt269I can contribute to HBeAg negative infections and liver disease progression in chronic patients with genotype C infections via mitochondrial stress mediated IFN-I production.

Keywords: Hepatitis B virus, HBV e antigen (HBeAg) negative infection, Genotype C, Mitochondrial stress, Type I Interferons

Received: 03 May 2019; Accepted: 09 Jul 2019.

Edited by:

Takanobu Kato, National Institute of Infectious Diseases (NIID), Japan

Reviewed by:

Masaya Sugiyama, National Center For Global Health and Medicine, Japan
Koichi Watashi, National Institute of Infectious Diseases (NIID), Japan  

Copyright: © 2019 Lee, Choi, Yang, Lee, Choe, Kook and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Bum-Joon Kim, Seoul National University College of Medicine, Seoul, South Korea,