Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K08482
• 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: National Institute of Infectious Diseases
• Principal Investigator: Kato Takanobu 国立感染症研究所, ウイルス第二部, 室長 (20333370)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: B型慢性肝炎 / 臨床的治癒 / 遺伝子変異 / cccDNA

Outline of Final Research Achievements

The substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region has been reported as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the HBV lifecycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L.The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

現行のB型慢性肝炎治療では臨床的治癒が治療目標とされている。これまでにB型慢性肝炎症例のHBVゲノムの解析から、コア領域I97Lの変異が臨床的治癒に関与していることが報告されている。そこで、このI97Lの変異がHBVのライフサイクルに与える影響を解析した。その結果、I97L変異は一本鎖ゲノムを持つ未熟なウイルスを産生し、cccDNA生成効率の低下に関与してることが明らかとなった。そして、このcccDNA合成効率の低下が、感染HBV量を減少を引き起こし臨床的治癒の成立に寄与していると考えられた。臨床的治癒の達成のためには感染細胞中のcccDNA量を低下させる治療法の確立が必要と考えられた。