Murali Ganesan1,2, Weimin Wang3, Saumi Mathews3, Edward Makarov3, Moses New-Aaron1,4, Raghubendra Singh Dagur1,2, Antje Malo5, Ulrike Protzer5,6, Kusum K Kharbanda1,2, Carol A Casey1,2, Larisa Y Poluektova3, Natalia A Osna1,2. 1. Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA. 2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA. 3. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA. 4. Department of Environmental Health, Occupational Health and Toxicology, University of Nebraska Medical Center, Omaha, Nebraska, USA. 5. Institute of Virology, Helmholtz Zentrum München, Munich, Germany. 6. German Centre for Infection Research (DZIF), Munich, Hamburg, Heidelberg, Germany.
Abstract
BACKGROUND AND AIMS: Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS: We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS: We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.
BACKGROUND AND AIMS: Approximately 3.5% of the global population is chronically infected with Hepatitis B Virus (HBV), which puts them at high risk of end-stage liver disease, with the risk of persistent infection potentiated by alcohol consumption. However, the mechanisms underlying the effects of alcohol on HBV persistence remain unclear. Here, we aimed to establish in vivo/ex vivo evidence that alcohol suppresses HBV peptides-major histocompatibility complex (MHC) class I antigen display on primary human hepatocytes (PHH), which diminishes the recognition and clearance of HBV-infected hepatocytes by cytotoxic T-lymphocytes (CTLs). METHODS: We used fumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chain knock-out (FRG-KO) humanized mice transplanted with human leukocyte antigen-A2 (HLA-A2)-positive hepatocytes. The mice were HBV-infected and fed control and alcohol diets. Isolated hepatocytes were exposed ex vivo to HBV 18-27-HLA-A2-restricted CTLs to quantify cytotoxicity. For mechanistic studies, we measured proteasome activities, unfolded protein response (UPR), and endoplasmic reticulum (ER) stress in hepatocytes from HBV-infected humanized mouse livers. RESULTS AND CONCLUSIONS: We found that alcohol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to the suppression of proteasome function and ER stress induction, which diminished both the processing of HBV peptides and trafficking of HBV-MHC class I complexes to the hepatocyte surface. This alcohol-mediated decrease in MHC class I-restricted antigen presentation of the CTL epitope on target hepatocytes reduced the CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.
Authors: Robert Thimme; Stefan Wieland; Carola Steiger; John Ghrayeb; Keith A Reimann; Robert H Purcell; Francis V Chisari Journal: J Virol Date: 2003-01 Impact factor: 5.103
Authors: Murali Ganesan; Joseph Hindman; Brittany Tillman; Lee Jaramillo; Larisa I Poluektova; Barbara A French; Kusum K Kharbanda; Samuel W French; Natalia A Osna Journal: Exp Mol Pathol Date: 2015-09-25 Impact factor: 3.362
Authors: Atefeh Khakpoor; Yi Ni; Antony Chen; Zi Zong Ho; Vincent Oei; Ninghan Yang; Reshmi Giri; Jia Xin Chow; Anthony T Tan; Patrick T Kennedy; Mala Maini; Stephan Urban; Antonio Bertoletti Journal: J Virol Date: 2019-02-05 Impact factor: 5.103
Authors: A Bertoletti; A Costanzo; F V Chisari; M Levrero; M Artini; A Sette; A Penna; T Giuberti; F Fiaccadori; C Ferrari Journal: J Exp Med Date: 1994-09-01 Impact factor: 14.307