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.
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