title: Low hepatitis B virus-specific T-cell response in males correlates with high regulatory T-cell numbers in murine models.
abstract: Hepatitis B virus (HBV) infection shows significant gender-related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender-associated differences in HBV replication and viral protein levels may be associated with distinct HBV-specific immune responses in the host. In the present study, we examined the impact of gender on HBV-specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus transgenic mouse model. Consistent with previous reports, significantly higher HBV DNA and protein levels were detected in male compared to female mice. Although hydrodynamic injection with the HBV genome resulted in similar numbers of intrahepatic HBV-specific cluster of differentiation 8-positive (CD8+) T cells, their functionality was significantly reduced in males and correlated with higher numbers of intrahepatic regulatory T cells (Tregs). Similar effects were observed in woodchuck hepatitis virus transgenic mice immunized with a DNA prime-recombinant adenovirus boost vaccination protocol. Male mice showed functionally suppressed woodchuck hepatitis virus-specific CD8+T-cell responses in the liver and significantly higher numbers of intrahepatic Tregs compared to females. Blockade of Treg responses in male mice led to augmented effector functions of specific CD8+T cells and subsequently improved virus control in both models of transient and persistent hepadnaviral infection.
  
  
  
  The functionality of virus-specific CD8+T cells in male mice was suppressed by intrahepatic Tregs and inversely correlated with levels of hepadnaviral DNA and viral protein; the induction of intrahepatic Tregs by viral replication and/or protein levels may explain the gender-related differences in the outcomes of HBV infection and limit the success of immunotherapeutic strategies in male patients. (Hepatology 2017;66:69-83).
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.|Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
authors.forename: Anna D
authors.initials: AD
authors.lastname: Kosinska
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Leila
authors.initials: L
authors.lastname: Pishraft-Sabet
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Weimin
authors.initials: W
authors.lastname: Wu
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.|Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Lenart
authors.affiliation: Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
authors.forename: Jieliang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Kirsten K
authors.initials: KK
authors.lastname: Dietze
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Thekla
authors.initials: T
authors.lastname: Kemper
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.|NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Shiou-Hwei
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.affiliation: Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.|Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Roggendorf
authors.affiliation: Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006509:Hepatitis B / Q000276:immunology* / Q000517:prevention & control; D017325:Hepatitis B Vaccines / Q000008:administration & dosage; D006515:Hepatitis B virus / Q000276:immunology*; D007111:Immunity, Cellular / Q000502:physiology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011897:Random Allocation; D012307:Risk Factors; D012737:Sex Factors; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014611:Vaccination / Q000379:methods
chemical_list: D017325:Hepatitis B Vaccines