Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection

Authors

  • Yu-Fen Fan,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Cheng-Chan Lu,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Wen-Chi Chen,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Wei-Jen Yao,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Hui-Ching Wang,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Ting-Tsung Chang,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Huan-Yao Lei,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Ai-Li Shiau,

    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
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  • Ih-Jen Su M.D.,

    Corresponding author
    1. From the Graduate Institutes of Basic Medicine and Microbiology, and Departments of Medicine, Pathology, and Nuclear Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan
    • Department of Pathology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, Taiwan. fax: (886) 2-23934172.
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Abstract

Several types of naturally occurring pre-S mutants in sera or liver tissues in patients with chronic hepatitis B virus (HBV) infection have been identified. To clarify the prevalence and significance of emergence of pre-S mutants, 140 sera and 18 resected livers from patients with HBV were studied. Replicative status was designated as high, intermediate, and low based on the HBV-DNA levels in serum or the expression of HBV antigens in liver. In vitro transfection and Western blot analysis were performed to characterize expression and secretion of HBsAg by the mutant constructs. Five major types (I to V) of pre-S deletion mutants in serum and liver and 2 types (VI and VII) in liver were identified. Pre-S mutant was 6.4% at high replicative phase, 13% at intermediate, and 37.5% at low or nonreplicative phases in serum. In livers, the same tendency existed: pre-S2 deletion mutants emerged and prevailed at a low replicative phase in hepatocytes that expressed a novel marginal pattern of HBsAg and usually clustered in groups. The deletion sequence of pre-S2 region coincides with human leukocyte antigen-restricted T- and B-cell epitopes. In vitro HBsAg was retained in the hepatocytes and synthesis and secretion of major surface antigen decreased for most of the pre-S mutants. Pre-S mutants prevailed with evolution of chronic HBV, probably under immune pressure. Emergence of pre-S mutants may account for the life-long persistence and discrepancy of HBsAg in serum and liver in HBV and may confer growth advantage in view of the clustering proliferation of hepatocytes harboring pre-S2 mutant.

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