Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection

Authors

  • Shujuan Lv,

    1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
    2. Department of Microbiology, Anhui Medical University, Hefei, China
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  • Jun Wang,

    Corresponding author
    1. School of Life Sciences and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
    • Address reprint requests to: Haiming Wei, M.D., Zhigang Tian, Ph.D., or Jun Wang, Ph.D., School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei City, 230027, Anhui, China. E-mail: ustcwhm@ustc.edu.cn, tzg@ustc.edu.cn, or jwang699@ustc.edu.cn; Fax: +86-551-6360-6783.

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  • Shuang Dou,

    1. School of Life Sciences and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
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  • Xianzhu Yang,

    1. School of Life Sciences and Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, China
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  • Xiang Ni,

    1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
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  • Rui Sun,

    1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
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  • Zhigang Tian,

    Corresponding author
    1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
    • Address reprint requests to: Haiming Wei, M.D., Zhigang Tian, Ph.D., or Jun Wang, Ph.D., School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei City, 230027, Anhui, China. E-mail: ustcwhm@ustc.edu.cn, tzg@ustc.edu.cn, or jwang699@ustc.edu.cn; Fax: +86-551-6360-6783.

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  • Haiming Wei

    Corresponding author
    1. Institute of Immunology, Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China
    • Address reprint requests to: Haiming Wei, M.D., Zhigang Tian, Ph.D., or Jun Wang, Ph.D., School of Life Sciences, University of Science and Technology of China, 443 Huangshan Road, Hefei City, 230027, Anhui, China. E-mail: ustcwhm@ustc.edu.cn, tzg@ustc.edu.cn, or jwang699@ustc.edu.cn; Fax: +86-551-6360-6783.

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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from Ministry of Science & Technology of China (973 Basic Science Project 2009CB522403, 2012CB519004) and the Natural Science Foundation of China (#81330071, #30730084).

Abstract

Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-α by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-α production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-α production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. Conclusion: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-α production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection. (Hepatology 2014;59:385–394)

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