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Ethanol attenuates presentation of cytotoxic T-lymphocyte epitopes on hepatocytes of HBV-infected humanized mice.

BACKGROUND & AIMS
3.5% of the global population chronically infected with Hepatitis B Virus (HBV) are under a high risk of end-stage liver disease outcomes, further potentiated by alcohol. However, the mechanisms behind 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. These mice were HBV-infected and fed control and ethanol diets. Isolated hepatocytes were ex vivo exposed 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 ethanol feeding attenuated HBV core 18-27-HLA-A2 complex presentation on infected hepatocytes due to suppression of proteasome function and ER stress induction, which diminishes both processing of HBV peptides and trafficking of HBV-MHC class I complexes to hepatocyte surface. This ethanol-mediated decrease in MHC class I-restricted antigen presentation of CTL epitope on target hepatocytes reduced CTL-specific elimination of infected cells, potentially leading to HBV-infection persistence, which promotes end-stage liver disease outcomes.