title: Lentiviral vector encoding ubiquitinated hepatitis B core antigen induces potent cellular immune responses and therapeutic immunity in HBV transgenic mice.
abstract: Predominant T helper cell type 1 (Th1) immune responses accompanied by boosted HBV-specific cytotoxic T lymphocyte (CTL) activity are essential for the clearance of hepatitis B virus (HBV) in chronic hepatitis B (CHB) patients. Ubiquitin (Ub) serves as a signal for the target protein to be recognized and degraded through the ubiquitin-proteasome system (UPS). Ubiquitinated hepatitis B core antigen (Ub-HBcAg) has been proved to be efficiently degraded into the peptides, which can be presented by major histocompatibility complex (MHC) class I resulting in stimulating cell-mediated responses. In the present study, lentiviral vectors encoding Ub-HBcAg (LV-Ub-HBcAg) were designed and constructed as a therapeutic vaccine for immunotherapy. HBcAg-specific cellular immune responses and anti-viral effects induced by LV-Ub-HBcAg were evaluated in HBV transgenic mice. We demonstrated that immunization with LV-Ub-HBcAg promoted the secretion of cytokines interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), generated remarkably high percentages of IFN-γ-secreting CD8(+) T cells and CD4(+) T cells, and enhanced HBcAg-specific CTL activity in HBV transgenic mice. More importantly, vaccination with LV-Ub-HBcAg could efficiently decreased the levels of serum hepatitis B surface antigen (HBsAg), HBV DNA and the expression of HBsAg and HBcAg in liver tissues of HBV transgenic mice. In addition, LV-Ub-HBcAg could upregulate the expression of T cell-specific T-box transcription factor (T-bet) and downregulate the expression of GATA-binding protein 3 (GATA-3) in spleen T lymphocytes. The therapeutic vaccine LV-Ub-HBcAg could break immune tolerance, and induce potent HBcAg specific cellular immune responses and therapeutic effects in HBV transgenic mice.
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Dai
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China. Electronic address: zangguoqin@126.com.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zang
authors.affiliation: Department of Infectious Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233,China. Electronic address: tzhhao@163.com.
authors.forename: Zhenghao
authors.initials: Z
authors.lastname: Tang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006509:Hepatitis B / Q000276:immunology*; D006512:Hepatitis B Core Antigens / Q000737:chemistry / Q000276:immunology*; D017325:Hepatitis B Vaccines / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007111:Immunity, Cellular; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D016086:Lentivirus / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry; D000098815:T-bet Transcription Factor
chemical_list: D006512:Hepatitis B Core Antigens; D017325:Hepatitis B Vaccines; D015395:Histocompatibility Antigens Class I; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D025801:Ubiquitin
keywords: Cytotoxic T lymphocyte; Hepatitis B core antigen; Lentiviral vector; Ubiquitin; Virus immunotherapy