Temporal pathogenesis of experimental neonatal woodchuck hepatitis virus infection: Increased initial viral load and decreased severity of acute hepatitis during the development of chronic viral infection

Authors

  • Paul J. Cote,

    Corresponding author
    1. Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Rockville, MD
    • Division of Molecular Virology and Immunology, Georgetown University Medical Center, 13 Taft Court, Suite 101, Rockville, MD 20850. Fax: 301-309-1553
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  • Ilia Toshkov,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Christine Bellezza,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Mary Ascenzi,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Carol Roneker,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Lou Ann Graham,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Betty H. Baldwin,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • Karen Gaye,

    1. Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Rockville, MD
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  • Ikuo Nakamura,

    1. Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Rockville, MD
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  • Brent E. Korba,

    1. Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Rockville, MD
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  • Bud C. Tennant,

    1. Gastrointestinal Unit, Department of Clinical Sciences, New York State College of Veterinary Medicine, Cornell University, Ithaca, NY
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  • John L. Gerin

    1. Division of Molecular Virology and Immunology, Department of Microbiology and Immunology, Georgetown University Medical Center, Rockville, MD
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Abstract

Acute hepatitis B virus (HBV) infections either resolve or progress to chronicity. Identification of early deviations in host-virus responses associated with these outcomes can further differentiate cause-effect mechanisms that initiate and maintain chronicity. Neonatal woodchucks were infected experimentally with the woodchuck hepatitis virus (WHV) at 3 days of age. At 8 or 14 weeks of age (i.e., the early- or mid-acute stage of infection), whole blood and large surgical biopsies of the liver were obtained from infected animals and uninfected controls. These were stored for later correlating histopathologic responses and viral load with the subsequently determined outcome of infection. As of 1 year postinfection, half of the surgically treated infected woodchucks had developed self-limited infections, while the other half developed chronic infections. The self-limited outcome was characterized by decreased viral load in acute-phase liver and plasma and a generally robust acute hepatic inflammatory response. Comparisons at the same early time points revealed that the chronic outcome was characterized by increasing initial viral load in liver and plasma, and a detectable, but diminished, acute hepatic inflammation. These cotemporal comparisons indicate that there is an early host-response deviation during the acute phase of a developing chronic infection. Continued analysis of the tissues banked from this study will facilitate further temporal characterization of acute-phase mechanisms that determine resolution versus chronicity in WHV infection. Understanding such mechanisms may be useful in the rational design of therapy for established chronic HBV infection.

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