title: Identification of BST-2/tetherin-induced hepatitis B virus restriction and hepatocyte-specific BST-2 inactivation.
abstract: BST-2/tetherin is an interferon-inducible antiviral protein that blocks the release of various enveloped viruses, including HIV-1. Hepatitis B virus (HBV), a major cause of liver disease, belongs to the Hepadnaviridae family of enveloped DNA viruses. Whether BST-2 regulates HBV production is largely unknown. In this report, we have demonstrated that HBV particle release is modulated by BST-2 in a cell type-dependent fashion. In HEK293T cells, ectopically expressed or interferon-induced BST-2 strongly inhibited HBV release. BST-2 co-localized with HBV surface protein at multivesicular bodies (MVBs) and physically interacted with HBV particles. However, exogenous BST-2-induced HBV restriction was weak in Huh-7 hepatoma cells, and the interferon-induced anti-HBV effect was independent of BST-2 induction in hepatic L02 cells. Notably, HBV could promote HIV-1 ΔVpu virus release from BST-2-positive HepG2 hepatoma cells but not HeLa cells, whereas Vpu failed to efficiently inhibit BST-2-induced HBV restriction. HBx exhibited an enhanced interaction and co-localization with BST-2 in hepatocytes. These observations indicate that BST-2 restricts HBV production at intracellular MVBs but is inactivated by HBV through a novel mechanism requiring hepatocyte-specific cellular co-factors or a hepatocyte-specific environment. Further understanding of BST-2-induced HBV restriction may provide new therapeutic targets for future HBV treatments.
authors.affiliation: 1] Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China [2] Department of Hepatology, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Mingyu
authors.initials: M
authors.lastname: Lv
authors.affiliation: 1] Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China [2] School of Pharmaceutical Sciences, Jilin University, Changchun, P. R. China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Han
authors.affiliation: School of Life Sciences, Jilin University, Changchun, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun, P. R. China.
authors.forename: Yulai
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Hepatology, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: 1] Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, P. R. China [2] Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D002451:Cell Compartmentation; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000821:virology*; D054298:Human Immunodeficiency Virus Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D060149:Tetraspanin 30 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D014771:Virion / Q000378:metabolism; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D006514:Hepatitis B Surface Antigens; D054298:Human Immunodeficiency Virus Proteins; D060149:Tetraspanin 30; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C057628:hepatitis B virus X protein; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins