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.
[1]Fudan Univ, Huashan Hosp, Dept Infect Dis, Shanghai 200040, Peoples R China;
[2]Fudan Univ, Shanghai Med Coll, Key Lab Med Epigenet & Metab, Sch Basic Med Sci,Inst Biomed Sci, Shanghai 200032, Peoples R China;
[3]Fudan Univ, Sch Basic Med Sci,Shanghai Med Coll, Minist Educ,Natl Hlth Commiss,Chinese Acad Med Sc, Key Lab Med Mol Virol,Dept Microbiol & Parasitol, Shanghai 200032, Peoples R China;
[4]Fudan Univ, Childrens Hosp, Shanghai 201199, Peoples R China
(8.0+极速模式)