Anna D Kosinska1,2, Leila Pishraft-Sabet1, Weimin Wu1, Zhong Fang2,3, Marzena Lenart4, Jieliang Chen3, Kirsten K Dietze1, Cong Wang2, Thekla Kemper1, Yong Lin1, Shiou-Hwei Yeh5,6, Jia Liu1, Ulf Dittmer1, Zhenghong Yuan2,3, Michael Roggendorf1, Mengji Lu1. 1. Institute of Virology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany. 2. Key Laboratory of Medical Molecular Virology, Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China. 3. Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, People's Republic of China. 4. Department of Clinical Immunology, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland. 5. Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan. 6. NTU Center for Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
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. CONCLUSION: 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).
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 virustransgenic 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. CONCLUSION: 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: Qian Li; Yan Yan; Jia Liu; Xuan Huang; Xiaoyong Zhang; Carsten Kirschning; Haifeng C Xu; Philipp A Lang; Ulf Dittmer; Ejuan Zhang; Mengji Lu Journal: Front Immunol Date: 2019-09-12 Impact factor: 7.561
Authors: Paulina Kur; Agnieszka Kolasa-Wołosiuk; Kamila Misiakiewicz-Has; Barbara Wiszniewska Journal: Int J Environ Res Public Health Date: 2020-04-11 Impact factor: 3.390