Basic research on developing new anti-HBV therapeutic strategy for cccDNA elimination by DOCK11 knockdown in HBV infected hepatocytes

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K07966
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kanazawa University
• Principal Investigator: LI YING-YI 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: HBV / cccDNA / DOCK11 / Retrograde trafficking / Golgi

Outline of Final Research Achievements

Hepatitis B virus (HBV) infection is difficult to cure owing to the persistence of cccDNA. Here, we identified DOCK11, a guanine nucleotide exchange factor (GEF), as a candidate druggable target for HBV. Interestingly, DOCK11 functionally associated with retrograde trafficking proteins in trans-Golgi network (TGN), AGAP2 and ARF1 together with HBV capsid, to open an alternative retrograde trafficking route of HBV capsid from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. cccDNA levels were strongly suppressed by shDOCK11. Surprisingly, combination of ETV plus shDOCK11 further reduced HBVDNA and cccDNA levels. Clinically, DOCK11 levels in the liver of patients with chronic hepatitis B were significantly reduced by entecavir treatment, and this reduction correlated with HBs antigen levels. Thus, DOCK11 could be a potential therapeutic target to prevent persistent HBV infection.

Free Research Field

molecular biology

Academic Significance and Societal Importance of the Research Achievements

エンテカビル（ETV）によってウイルス複製を継続的に抑制しても，感染肝細胞核内に容易に排除されることのない HBV cccDNAが残存して，再活性化と発癌を引起す可能性は高い。本研究では，cccDNAの維持を制御する一つの機構を初めて解明し，B型肝炎の治療に新しい治療法を提案した。