宿主限制因子MOV10下调HBV cccDNA的功能及机制研究

乙型肝炎病毒（HBV）共价闭合环状DNA（cccDNA）是病毒基因转录的模板，其持续稳定的存在于被感染的肝细胞核内是HBV感染慢性化的最主要原因。目前临床应用的抗HBV药物并不能有效清除cccDNA，导致患者停药后易复发。因此寻找和研究细胞内调控cccDNA的宿主因子并阐明其作用机制，进而开发靶向药物尤为重要。我们前期研究发现宿主限制因子RNA解螺旋酶MOV10能够抑制HBV复制的早期阶段，但不影响病毒颗粒进入细胞和病毒基因组进入细胞核。进一步的研究发现MOV10是通过下调cccDNA水平来抑制HBV的复制，但其调控cccDNA的具体作用机制尚不明确。因此本课题将从分子、细胞、小鼠及临床患者四个方面深入研究MOV10抑制病毒cccDNA的作用机制。该研究可能为清除肝细胞内病毒cccDNA提供新的治疗靶点及研究思路，具有重要的临床应用价值。

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), which persists in the nucleus of infected hepatocyte, is the template for all viral transcription and the key for HBV persistence. Current available anti-HBV drugs cannot efficiently eliminate viral cccDNA, and HBV recurrence generally occurs upon drug discontinuation. Therefore, it is of great importance to study novel host factors that can regulate cccDNA and elucidate the underlying mechanisms in order to develop cccDNA-targeted drugs. In our early study, we found that MOV10 can inhibit HBV replication at early stages of HBV life cycle, but not viral entry or the release of viral genome into the nucleus. Further study revealed that MOV10 decreases the level of viral cccDNA to inhibit HBV replication. However, the mechanisms whereby MOV10 decreases cccDNA remain to be fully elucidated. In this project, we will investigate the precise mechanism of MOV10-mediated inhibition of viral cccDNA by employing molecular biology, cell biology techniques, experimental mice and clinical species. Our study may open a new avenue to the development of novel anti-HBV therapeutics that may eliminate nuclear viral cccDNA, which is of great clinical significance.