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Human immunodeficiency virus enhances hepatitis C virus replication by differential regulation of IFN and TGF family genes§

Authors

  • Xiaozhen Zhang,

    1. Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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  • Marybeth Daucher,

    1. Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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  • Josue Baeza,

    1. Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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  • Cheol-Woo Kim,

    1. Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
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  • Rodney Russell,

    1. Faculty of Medicine, Health Sciences Center, Memorial University of Newfoundland, St. John's, Canada
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  • Shyamasundaran Kottilil

    Corresponding author
    1. Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
    • Building 10-Magnuson Clinical Center, Room 11N204, 10 Center Drive, Bethesda, MD 20892.
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  • Disclaimer: The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government.

  • Conflicts of Interest: None of the authors have any conflicts of interest to report.

  • §

    This is a US Government work, and as such, is in the public domain in The United States of America.

Abstract

HIV co-infection significantly impacts the natural history of hepatitis C virus (HCV) by increasing plasma HCV viral load, accelerating liver disease progression, and reducing rates of HCV clearance. Cytokines play an important role in regulating hepatic inflammation and fibrogenesis during chronic HCV infection, yet the impact of HIV on cytokine expression is unknown. In this study, an HCV continuous infection cell culture system was modified to permit co-infection with HIV to test the hypothesis that virus-induced disregulation of immune-response genes, particularly interferons and TGF-β, may create a permissive environment for the initial establishment of HIV/HCV co-infection in the host. CCR5-expressing Huh-7.5 hepatoma cells were transduced with human CD4 antigen to allow HIV infection in vitro. Co-infection of CD4+ Huh-7.5 cells with HIV and HCV or co-culture of HIV-infected CD4+ Huh-7.5 cells and HCV-infected Huh-7.5 cells increased the level of HCV RNA compared to HCV mono-infection. Quantitative gene expression analysis revealed HIV-induced up regulation of most tested IFN family genes when compared to HCV or co-infection. HCV infection induced up regulation of many TGF family genes that were subsequently down-regulated in the presence of HIV or HIV/HCV. Interestingly, co-infection resulted in down regulation of several IFN genes and significant up regulation of TGF-β genes leading to an overall enhancement of HCV replication. These data suggest that HIV infection may influence HCV replication in vitro by increasing levels of HCV RNA, possibly through the differential regulation of endogenous IFN and TGF family genes. J. Med. Virol. 84:1344–1352, 2012. © 2012 Wiley Periodicals, Inc.

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