Elucidation of the mechanism for maintenance of hepatitis B virus cccDNA

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08001
• 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: Hamamatsu University School of Medicine
• Principal Investigator: Ito Masahiko 浜松医科大学, 医学部, 助教 (50385423)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: B型肝炎ウイルス / 潜伏感染 / HBV再活性化 / cccDNA / SET

Outline of Final Research Achievements

Chronic Hepatitis B virus (HBV) infection is a significant public health problem. Around a million people live with chronic HBV infection in Japan. The viral genome persists in the nuclei of hepatocytes, because covalently closed circular DNA (cccDNA) is stable in nondividing cells. However, the detailed molecular mechanisms underlying formation of cccDNA minichromosome and transcriptional reactivation of the viral cccDNA are poorly understood. From the exploration of the host factors associated with cccDNA, SET were identified. Knockdown or knockout of SET results in enhanced expression of cccDNA and pgRNA. In addition, SET was involved in cccDNA formation from double strand linear DNA via Histone H2AX. In this study, I elucidated that the involvement of SET on the HBV lifecycle and the molecular mechanism of latency and reactivation of HBV. The results obtained in this study lead to development of novel antiviral therapeutic agents or removal of cccDNA from the patients.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルスのキャリアは、本邦にはおよそ100～120万人(人口1％)、世界にはおよそ4億人いることが知られている。キャリアにおけるHBV活性化の抑制や無症候性キャリアからの感染拡大の防止は急務となっている。本研究により明らかになったSETによるHBV cccDNA形成・維持・再活性化機構に関する知見は、cccDNAの形成阻害、潜伏感染したcccDNAの排除、再活性化の抑制するための薬剤の開発に繋がり、多くの患者を救うための治療法に発展する。