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Ganesan, M.* ; Wang, W.* ; Mathews, S.* ; Makarov, E.* ; New-Aaron, M.* ; Dagur, R.S.* ; Malo, A. ; Protzer, U. ; Kharbanda, K.K.* ; Casey, C.A.* ; Poluektova, L.Y.* ; Osna, N.A.*

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

Alcohol. Clin. Exp. Res. 46, 40-51 (2022)
DOI PMC
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Antigen Presentation ; Etoh ; Hbv ; Hepatocytes; Cells; Inactivation; Binding; Alters
ISSN (print) / ISBN 0145-6008
e-ISSN 1530-0277
Zeitschrift Alcoholism: Clinical and Experimental Research
Quellenangaben Band: 46, Heft: 1, Seiten: 40-51 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen National Institute on Alcohol Abuse and Alcoholism (NIAAA), USA