Research Papers: Immunology:

Molecular dissection of HBV evasion from restriction factor tetherin: A new perspective for antiviral cell therapy

Kei Miyakawa, Satoko Matsunaga, Koichi Watashi, Masaya Sugiyama, Hirokazu Kimura, Naoki Yamamoto, Masashi Mizokami, Takaji Wakita and Akihide Ryo _

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Oncotarget. 2015; 6:21840-21852. https://doi.org/10.18632/oncotarget.4808

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Kei Miyakawa1, Satoko Matsunaga1, Koichi Watashi2, Masaya Sugiyama3, Hirokazu Kimura4, Naoki Yamamoto5, Masashi Mizokami3, Takaji Wakita2, Akihide Ryo1

1Department of Microbiology, Yokohama City University School of Medicine, Kanagawa 236–0004, Japan

2Department of Virology II, National Institute of Infectious Diseases, Tokyo 162–8640, Japan

3Department of Hepatic Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba 272–8516, Japan

4Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo 208–0011, Japan

5Department of Microbiology, National University of Singapore, Singapore 117597, Singapore

Correspondence to:

Akihide Ryo, e-mail: [email protected]

Keywords: hepatic injury, pyroptosis, Immunology and Microbiology Section, Immune response, Immunity

Received: July 04, 2015     Accepted: August 17, 2015     Published: August 27, 2015


Viruses have evolved various strategies to escape from the innate cellular mechanisms inhibiting viral replication and spread. Extensive evidence has highlighted the ineffectiveness of interferon (IFN) therapy against chronic hepatitis B virus (HBV) infection, implying the existence of mechanisms by which HBV evades IFN-induced antiviral responses. In our current study, we demonstrate that HBV surface protein (HBs) plays a crucial role in counteracting the IFN-induced antiviral response mediated by tetherin (also known as BST-2). The type I IFN treatment of HBV-producing cells marginally but significantly inhibited the release of HBsAg and viral DNA, but this release was recovered by the knockdown of tetherin. HBs can interact with tetherin via its fourth transmembrane domain thereby inhibiting its dimerization and antiviral activity. The expression of a tetherin mutant devoid of the HBs-binding domain promoted a prominent restriction of HBV particle production that eventually resulted in the alleviation of caspase-1-mediated cytotoxicity and interleukin-1β secretion in induced pluripotent stem cell (iPSC)-derived hepatocytes. Our current results thus reveal a previously undescribed molecular link between HBV and tetherin during the course of an IFN-induced antiviral response. In addition, strategies to augment the antiviral activity of tetherin by impeding tetherin-HBs interactions may be viable as a therapeutic intervention against HBV.

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