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; Department of Microbiology, Anhui Medical University, Hefei, China.
Hepatology. 2014 Feb;59(2):385-94. doi: 10.1002/hep.26654. Epub 2013 Dec 20.
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.
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.
乙型肝炎病毒（HBV）感染是全球范围内最常见的肝脏疾病病因。然而，由于目前基于干扰素（IFN）的治疗方法具有毒性副作用和边际疗效，因此需要改进抗病毒药物。在这里，我们报告来自 HBV 基因组的未甲基化胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸（HBV-CpG）以 Toll 样受体 9（TLR9）依赖的方式诱导浆细胞样树突状细胞（pDC）中 IFN-α的强烈表达。我们还鉴定了 HBV 基因组中能够抑制 HBV-CpG 诱导的 IFN-α产生的抑制性鸟嘌呤丰富的 ODN（HBV-ODN）。此外，含有 HBV-CpG 的纳米颗粒，称为 NP（HBV-CpG），逆转了 HBV-ODN 介导的 IFN-α产生的抑制作用，并对淋巴细胞具有强烈的免疫刺激作用。我们的结果表明，NP（HBV-CpG）可增强对乙型肝炎表面抗原（HBsAg）的免疫反应，并使对 rHBsAg 和 NP（HBV-CpG）免疫的小鼠的这种反应偏向 Th1 途径。此外，基于 NP（HBV-CpG）的治疗导致 HBV 的有效清除，并在 HBV 携带者小鼠中诱导抗 HBsAg 反应。
HBV 基因组中的内源性 HBV-CpG ODN 诱导 IFN-α 的产生，使得纳米颗粒包封的 HBV-CpG 可作为 HBsAg 疫苗佐剂，也可能代表治疗慢性 HBV 感染的有效治疗剂。
