靶向HBx的5'-三磷酸siRNA在pAAV-HBV转染的小鼠中引发有效的抗HBV

StephenW

Antiviral Res. 2018 Nov 15. pii: S0166-3542(18)30027-5. doi: 10.1016/j.antiviral.2018.11.006. [Epub ahead of print]
5'-triphosphate siRNA targeting HBx elicits a potent anti-HBV immune response in pAAV-HBV transfected mice.
Han Q1, Hou Z2, Yin C1, Zhang C1, Zhang J3.
Author information

1
    Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China.
2
    Laboratory of Immunology for Environment and Health, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), 19 Keyuan Road, Jinan 250014, China.
3
    Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, 44 Wenhua West Road, Jinan 250012, China. Electronic address: [email protected].

Abstract

RNA with 5'-triphosphate (3p-RNA) is recognized by RNA sensor RIG-I (retinoic acid-inducible gene I protein). Previously, we reported that small interfering RNA targeting HBx (3p-siHBx) could confer potent anti-hepatitis B virus (HBV) efficacy via HBx silencing and RIG-I activation. However, the characteristics of innate and adaptive immunity especially exhaustion profiles in the liver microenvironment in response to 3p-siHBx therapy have not been fully elucidated. Here, we observed that 3p-siHBx more significantly inhibited HBV replication in vivo. 3p-siHBx enhanced natural killer (NK) cell activation with KLRG1 and CD69 upregulation and interferon (IFN)-γ secretion. 3p-siHBx significantly reversed the exhaustion phenotype of CD8+ T cells, and augmented CD8+ T cell activation and function. Importantly, 3p-siHBx disrupted the differentiation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), accompanied by the reduction of the immunosuppressive cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β. 3p-siHBx also enhanced dendritic cell maturation. Further investigation showed that RIG-I was involved in 3p-siHBx-induced IFN-α, IFN-β, and IFN-λ production. Moreover, RIG-I activation in HBV+ hepatocytes would improve the recruitment of CD8+ T cells and NK cells. These results reveal that 3p-siHBx therapy can improve the immune microenvironment in HBV-carrier liver and inhibit HBV replication, indicating the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines or candidate drugs.
KEYWORDS:

HBV; Immunotherapy; RIG-I; RNA interference

PMID:
    30448255
DOI:
    10.1016/j.antiviral.2018.11.006

StephenW

抗病毒药物2018年11月15日.pii：S0166-3542（18）30027-5。 doi：10.1016 / j.antiviral.2018.11.006。 [提前打印]
靶向HBx的5'-三磷酸siRNA在pAAV-HBV转染的小鼠中引发有效的抗HBV免疫应答。
韩Q1，侯Z2，尹C1，张C1，张J3。
作者信息

1
    山东大学药学院免疫药物研究所，济南市文化西路44号，济南250012
2
    山东省科学技术大学（山东省科学院）山东分析测试中心环境与健康免疫学实验室，济南市科苑路19号，250014
3
    山东大学药学院免疫药物研究所，济南市文化西路44号，济南250012电子地址：[email protected]。

抽象

具有5'-三磷酸（3p-RNA）的RNA被RNA传感器RIG-1（视黄酸诱导型基因I蛋白）识别。以前，我们报道了针对HBx（3p-siHBx）的小干扰RNA可通过HBx沉默和RIG-I激活赋予有效的抗乙型肝炎病毒（HBV）功效。然而，响应于3p-siHBx疗法的肝脏微环境中先天性和适应性免疫特征，特别是耗尽特征的特征尚未完全阐明。在这里，我们观察到3p-siHBx更显着地抑制体内HBV复制。 3p-siHBx增强自然杀伤（NK）细胞活化与KLRG1和CD69上调和干扰素（IFN）-γ分泌。 3p-siHBx显着逆转了CD8 + T细胞的耗竭表型，并增强了CD8 + T细胞的活化和功能。重要的是，3p-siHBx破坏了髓源性抑制细胞（MDSC）和调节性T细胞（Treg）的分化，伴随着免疫抑制细胞因子白细胞介素（IL）-10和转化生长因子（TGF）-β的减少。 3p-siHBx还增强了树突细胞的成熟。进一步的研究表明，RIG-I参与了3p-siHBx诱导的IFN-α，IFN-β和IFN-λ的产生。此外，HBV +肝细胞中的RIG-I活化将改善CD8 + T细胞和NK细胞的募集。这些结果表明3p-siHBx疗法可改善HBV载体肝脏中的免疫微环境并抑制HBV复制，表明RIG-I配体作为病毒疫苗或候选药物的分子佐剂的潜在用途。
关键词：

HBV;免疫治疗; RIG-I; RNA干扰

结论：
    30448255
DOI：
    10.1016 / j.antiviral.2018.11.006

newchinabok

StephenW 发表于 2018-11-19 17:27
抗病毒药物2018年11月15日.pii：S0166-3542（18）30027-5。 doi：10.1016 / j.antiviral.2018.11.006。 [提 ...

国内不看，评职称，写论文用的，也没有投资者投资开发

StephenW

回复 newchinabok 的帖子

为什么这项研究有意义:
1. RNAi可用于沉默基因，也可激活病毒传感蛋白(PAMP);
2. 3p-siHBX 可用于沉默基因HBX, 也可激活RNA  sensor RIG-I  (retinoic acid–inducible  gene  I  protein)传感器RIG-I（维甲酸酸诱导基因I蛋白）;
3. 3p-siHBX是一种两用抗病毒药物.

SB 9200 ( Inarigivir)也是RIG-I激动剂)