51. IL-21-based therapies induce clearance of hepatitis B virus persistence in mouse models
- Author
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J.D. Wu, Youhua Xie, Jiming Zhang, Jing Liu, Gaiyun Li, Qiang Deng, Yuanfei Zhu, Zhongliang Shen, Jun Wang, and Mengjun Luo
- Subjects
0301 basic medicine ,Male ,Adoptive cell transfer ,Cellular immunity ,Hepatitis B virus ,CD3 Complex ,mouse model ,Medicine (miscellaneous) ,clearance ,cellular immunity ,Biology ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,IL-21 ,medicine ,Animals ,Humans ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Hepatitis ,Mice, Inbred BALB C ,Hepatitis B Surface Antigens ,Interleukins ,cccDNA ,Dependovirus ,medicine.disease ,Hepatitis B ,Virology ,Adoptive Transfer ,Disease Models, Animal ,030104 developmental biology ,Liver ,DNA, Viral ,030211 gastroenterology & hepatology ,Replicon ,DNA, Circular ,CD8 ,Spleen ,Research Paper - Abstract
Chronic hepatitis B virus (HBV) infection causes hepatitis, liver cirrhosis and hepatocellular carcinoma. Covalently closed circular DNA (cccDNA) is the sole viral transcription template and not affected by current treatment options, constituting a key determinant of HBV persistence. Novel therapeutics with demonstrable effectiveness against cccDNA are required. Methods: Previously, we established an HBV persistence mouse model using replicon plasmid derived from a clinical isolate (termed BPS) and identified IL-21 as a potent clearance-inducer. We also described another persistence mouse model based on cccDNA mimics produced in vivo termed recombinant cccDNA (rcccDNA). In this work, effectiveness of IL-21-based gene and cellular therapies was tested using these models. Results: In both models of HBV persistence, single injections with adeno-associated virus (AAV) expressing murine IL-21 highly efficiently induced clearance of both HBV markers from serum, and more importantly, BPS DNA and rcccDNA from mouse liver. Mechanistically, IL-21-induced clearance was associated with activation and liver infiltration of CD8+ T cells, and CD8 antibody injections negatively affected AAV-IL-21 effectiveness. More notably, adoptive transfer of CD8+ T cells from AAV-IL-21-cured mice engendered clearance in acceptor HBV persistence mice. Furthermore, cured mice were protected against re-challenge with long-lived memory. Most significantly, infusion of splenocytes from treatment-naive mice stimulated ex vivo with IL-21 protein and HBV antigen could also induce clearance in treatment-naive mice. Conclusion: These data demonstrate IL-21-based gene and cellular therapies as valid candidates for treating chronic HBV infections, with potential in removing cccDNA-harboring hepatocytes via activated CD8+ T cells accompanied by long-term protective memory.
- Published
- 2019