Alcohol and Hepatitis C Virus–Interactions in Immune Dysfunctions and Liver Damage

Authors

  • Gyongyi Szabo,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • Jack R. Wands,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • Ahmet Eken,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • Natalia A. Osna,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • Steven A. Weinman,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • Keigo Machida,

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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  • H. Joe Wang

    1. From the Department of Medicine (GS), University of Massachusetts Medical School, Worcester, Massachusetts; The Liver Research Center (JRW, AE), Brown Alpert Medical School and Rhode Island Hospital, Providence, Rhode Island; Department Internal Medicine (NAO), University of Nebraska Medical Center and VA Medical Center, Omaha, Nebraska; Liver Center and Department of Internal Medicine (SAW), University of Kansas Medical Center, Kansas City, Kansas; Southern California Research Center for ALPD and Cirrhosis (KM), Departments of Molecular Microbiology and Immunology (KM), University of Southern California, Keck School of Medicine, Los Angeles, California; and Division of Metabolism and Health Effects (HJW), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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Reprint requests: Gyongyi Szabo, MD, PhD, Department of Medicine, LRB215 University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605; Tel.: 508-856-5275; Fax: 508-856-4770; E-mail: gyongyi.Szabo@umassmed.edu and H. Joe Wang, PhD, Division of Metabolism and Health Effect, National Institute on Alcohol Abuse and Alcoholism, 5635 Fishers Lane, Room 2029, MSC 9304, Bethesda, MD 20892-9304; Tel.: 301-451-0747; Fax: 301-594-0673; E-mail: wangh4@mail.nih.gov

Abstract

Hepatitis C virus infection affects 170 million people worldwide, and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis, and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV-infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis, but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these processes by alcohol and HCV produces an environment of impaired antiviral immune response, greater hepatocellular injury, and activation of cell proliferation and dedifferentiation.

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