Ethanol attenuates presentation of cytotoxic T‐lymphocyte epitopes on hepatocytes of HBV‐infected humanized mice. (23rd November 2021)

• Record Type: Journal Article
• Authors: Ganesan, Murali; Wang, Weimin; Mathews, Saumi; Makarov, Edward; New‐Aaron, Moses; Dagur, Raghubendra Singh; Malo, Antje; Protzer, Ulrike; Kharbanda, Kusum K.; Casey, Carol A.; Poluektova, Larisa Y.; Osna, Natalia A.
• Is Part Of: Alcoholism. Volume 46:Number 1(2022)
• Page Start: 40
• Page End: 51
• Publication Date: 2021-11-23
• Subjects: antigen presentation -- EtOH -- HBV -- hepatocytes; Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.14740
• Languages: English
• ISSNs: 0145-6008

Abstract

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. Abstract : Hepatitis B virus infection (HBV) outcomes are worsened in patients with alcohol use disorder (AUD), but the mechanisms are not clear. In this study, we found that in vivo exposure to ethanol suppresses proteasome function and increased ER stress thereby decreasing HBV peptide‐MHC class I complex expression on hepatocyte surface, which attenuates the ability of HBV specific CTLs to eliminate the virus‐infected hepatocytes. Collectively, all these events may promote HBV‐infection persistence and development of HBV‐associated end‐stage liver disease outcomes.