Hepatitis B virus (HBV) infection is one of the leading causes of hepatic decompensation and hepatocellular carcinoma worldwide; approximately 400 million people are infected with HBV. Due to the high prevalence of alcohol consumption in the general population, a significant portion of chronic HBV patients are also chronic alcohol abusers. Alcohol intake prolongs HBV persistence leading to establishment of chronic hepatitis. The mechanisms of rapid HBV infection progression and severe outcomes in alcohol-consuming patients are not clear. The virus is not cytopathogenic, and effective clearance requires the induction of an adaptive immune response, mainly via virus-specific CD8+ cytotoxic T lymphocytes (CTLs), which recognize viral peptide-major histocompatibility complex (MHC) class I on infected hepatocytes. While many studies have focused on alcohol-induced impairments of the immune response, information on how alcohol masks the presentation of HBV peptide-MHC class I complex on infected hepatocyte surfaces for escaping recognition by CTLs is missing. Therefore, the main focus of this study is to understand the effects of ethanol metabolism on the expression of the HBV peptide-MHC class I complex on HBV-infected hepatocytes. The presentation of this complex on cell membranes requires antigen processing by proteasomes in the cytosol, loading of peptides into MHC class I, assembly of peptide-loading complex with transporters for antigen presentation (TAP), its stabilization by tapasin in endoplasmic reticulum, and trafficking of this complex via trans-Golgi to the hepatocyte surface. Almost all of these steps are interferon-gamma dependent. Recently, we have found that the ethanol metabolite, acetaldehyde (Ach), suppresses HBV core peptide 18-27 presentation on HBV+ hepatocytes, which is accompanied by dysregulation of proteasome function, reduction in TAP1/tapasin expression and Golgi fragmentation, all of which work in combination to impair HBV-MHC class I complex presentation on infected hepatocytes. Based on these preliminary data, we put forth the hypothesis that ethanol metabolism decreases the display of HBV peptide-MHC class I complex on the hepatocyte surface by impairing viral peptide cleavage by the proteasome and by disrupting peptide-MHC class I trafficking to the cell surface. We will utilize a variety of state-of-the art and innovative techniques to test our novel hypothesis. The three specific aims of the proposed study are to: 1) Examine the effects of ethanol metabolism and HBV on antigenic peptide processing for MHC class I-restricted antigen presentation on hepatocytes; 2) Determine how ethanol metabolism affects the trafficking of peptide loading complex for expressing HBV peptide-MHC class I on hepatocytes; 3) Validate the results of specific aims 1-2 using chimeric mice double-reconstituted with human hepatocytes and a human immune system. Completion of the proposed studies will help in the development of treatment modalities for preventing the persistence of hepatitis B in alcohol abusing patients.

Public Health Relevance

Epidemiological and clinical studies reveal more rapid progression and greater severity of Hepatitis B Virus (HBV) infection in heavy alcohol drinkers. This project seeks to examine the novel mechanisms by which alcohol causes HBV persistence. Successful completion of these studies will aid in the development of therapeutic strategies for preventing persistence of HBV-infection in alcohol consumers.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Wang, Joe
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University of Nebraska Medical Center
Internal Medicine/Medicine
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United States
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