PS-075
AAV-delivered IL-21 activates CD8+ T-cells to clear HBV replicon
plasmid and cccDNA in mice
Zhongliang Shen1, Jing Liu2, Jingwen Wu1, Yuanfei Zhu2, Gaiyun Li2,
JunWang2, Mengjun Luo2, Qiang Deng2, Jiming Zhang1, Youhua Xie2.
1Huashan Hospital, Fudan University, Shanghai, China; 2School of Basic
Medical Sciences, Fudan University, Shanghai, China
Email: [email protected]
Background and aims: Chronic hepatitis B virus (HBV) infection
causes hepatitis, liver cirrhosis and hepatocellular carcinoma. HBV
covalently closed circular DNA (cccDNA) is the sole viral transcription
template in infected hepatocytes and is not cleared by current
treatment options, thus constituting a key factor underlying HBV
persistence in vivo. Previously, we established a mouse HBV
persistence model based on hydrodynamic injection of HBV replicon
plasmid and identified interleukin-21 (IL-21) as a potent regulator of
HBV clearance in mice. We also recently described another HBV
persistence mouse model based on cccDNA mimic termed recombinant
cccDNA (rcccDNA) that is produced in vivo. Novel therapeutics
with demonstrable effectiveness against cccDNA need to be
developed.
Method: Antiviral effects of IL-21 were evaluated in HBV persistence
models via adeno-associated virus (AAV)-IL-21 injection. Antibody
block and adoptive transfer of immune cells were performed to
investigate the cells involved in IL-21-mediated HBV clearance. To
determine the long-lasting memory of antiviral effects, the cured
mice were re-challenged with HBV.
Results: AAV-IL-21 treatments efficiently clears serum HBV markers
and intrahepatic HBV replicon and rcccDNA. Antibodies against CD8+
T cells delayed IL-21-mediated HBV clearance. Adoptive transfer of
splenic CD8+ T cells from the cured mice engenders clearance of HBV
persistence in acceptor mice. IL-21-induced CD8+ T cell response
harbors long-lasting memory that provides prolonged protection for
the cured mice.
Conclusion: Our results demonstrate IL-21 as a sound basis for novel
therapeutics against chronic HBV infection, with potential in
removing cccDNA-harboring hepatocytes via activated CD8+ T cell
responses and establishing subsequent long-term protection. 作者: StephenW 时间: 2019-3-31 12:49