2021 Fiscal Year Annual Research Report
Basic research on developing new anti-HBV therapeutic strategy for cccDNA elimination by DOCK11 knockdown in HBV infected hepatocytes
| Project/Area Number |
18K07966
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
李 影奕 金沢大学, 医学系, 博士研究員 (70401940)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
本多 政夫 金沢大学, 保健学系, 教授 (00272980)
|
|---|
| Project Period (FY) |
2018-04-01 – 2022-03-31
|
| Keywords | cccDNA / DOCK11 / AGAP2 / ARF1 / antivirus therapy |
|---|
| Outline of Annual Research Achievements |
cccDNA is reservoir for viral persistence and a key obstacle for a cure of CHB. A small number of cccDNA-positive hepatocytes might be a source for viral reactivation during immune suppression. We established a new HCC cell line (named KM) in order to elucidate the host factors required for HBV persistence. We identified human DOCK11 as a one of candidate host factors to maintain cccDNA in KM cells. Our data revealed that DOCK11 activated retrograde trafficking of HBV from early endosomes to the TGN and then to the endoplasmic reticulum, thereby avoiding lysosomal degradation. Moreover, DOCK11 partners AGAP2 and ARF1, essential regulators of retrograde trafficking in the Golgi, were identified using LC-Ms/Ms and were involved in HBV trafficking. Furthermore, DOCK11 and AGAP2 might accelerate HBV recycling possibly through the TGN-ER to nucleus pathway. Additionally, in vivo mouse experiments, DOCK11 shRNA decreased the level of cccDNA in C57BL6 mice which were received AAV-HBV1.3 particles. Clinically, DOCK11 levels in the liver of patients with CHB were significantly reduced by ETV treatment, and this reduction correlated with HBs antigen levels. Thus, DOCK11 might be a candidate druggable target for HBV cure.
|
