Hepatitis B virus mutations affecting synthesis of relaxed-circular viral DNA : Relation to disease severity

影响松弛环状病毒 DNA 合成的乙型肝炎病毒突变：与疾病严重程度的关系

• 批准号: 18599003
• 负责人: OHKAWA Kazuyoshi
• 金额: $ 2.39万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18599003/
• 关键词: Hepatitis B virus (HBV); HBV mutation; Relaxed-circular (RC) HBV DNA

There are three kinds of viral HBV DNAs, the single-stranded (SS) HBV DNA, the double-stranded linear (DL) HBV DNA and the double-stranded relaxed-circular (RC) HBV DNA, in HBV-infected cells. Among them, only the RC HBV DNA can form the mature HBV virion with infectivity. In this study, we investigated HBV mutations affecting RC HBV DNA synthesis and its involvement in the pathogenesis of HBV-related liver diseases.1) Identification of the accountable HBV mutation for an increase of RC HBV DNA synthesis in a patient with tvpe B chronic hepatitis showing lethal exacerbation.We experienced a patient with type B chronic hepatitis showing lethal disease exacerbation. From serum samples at 1 year before exacerbation (P1) and after exacerbation (P2), the full-length HBV DNAs were obtained and designated as HBV P1 and P2 strains. When the HBV P1 and P2 strains were expressed in the cultured cells, the RC HBV DNA level was higher in P2-expressing cells than in P1-expressing ones. Further deta … More iled analyses showed that a G-to-A mutation at nt 2790 from P1 to P2 was an accountable mutation for an increase of RC HBV DNA synthesis and the subsequent disease deterioration in this patient.2) Relation of HBV mutations affecting the the RC HBV DNA sythesis to the disease severity in type B acute and chronic liver disease.Thus far, three regions, α (nt2817-2936), γ (nt1909-2141) and δ (nt1373-1589), have been shown to be cis-acting elements which play an important role in RC HBV DNA synthesis. In this study, we carried out sequencing analysis of full-length HBV DNA in 44 patients with type B chronic liver disease and 15 patients with type B acute liver disease. The degree of mutations in the α, γ and δ regions was correlated with the disease severity. In patients with chronic liver disease, the degree of mutations in the α and δ regions was higher in patients with cirrhosis and hepatocellular carcinoma than in those with chronic hepatitis (p=0.006 and p=0.05). As for patients with acute liver disease, patients with fulminant hepatitis had the higher degree of mutations in the α, and γ regions than those with acute self-limited hepatitis (p=0.03 and p=0.01). These results suggest that the high degree of mutations within these regions may affect RC HBV DNA synthesis and viral replicative competence, resulting in the serious liver disease in both acute and chronic HBV infection. Less

HBV感染细胞中存在三种HBV DNA，即单链（SS）HBV DNA、双链线性（DL）HBV DNA和双链松弛环状（RC）HBV DNA。其中，只有RC HBV DNA能形成具有感染性的成熟HBV病毒粒子。本研究旨在探讨HBV变异对RC HBV DNA合成的影响及其在HBV相关性肝病发病机制中的作用。1）1例慢性B肝炎致死性加重患者RC HBV DNA合成增加的HBV变异的鉴定。从急性加重前（P1）和急性加重后（P2）1年的血清样本中获得全长HBV DNA，并将其命名为HBV P1和P2株。当HBV P1和P2株在培养细胞中表达时，表达P2的细胞中RC HBV DNA水平高于表达P1的细胞。更多详情 ...更多信息 研究结果表明，2790位核苷酸P1 → P2的G → A突变是导致该患者RC HBV DNA合成增加和病情恶化的原因; 2）影响RC HBV DNA合成的HBV突变与B型急慢性肝病病情严重程度的关系（nt 2817 -2936）、γ（nt 1909 -2141）和δ（nt 1373 -1589）是顺式作用元件，在RC HBV DNA合成中起重要作用。本研究对44例B型慢性肝病和15例B型急性肝病患者的HBV DNA进行了全序列分析。α、γ和δ区的突变程度与疾病严重程度相关。在慢性肝病患者中，肝硬化和肝细胞癌患者的α和δ区突变程度高于慢性肝炎患者（p=0.006和p=0.05）。在急性肝病患者中，重型肝炎患者α、γ区的突变程度高于急性自限性肝炎患者（p=0.03和p=0.01）。这些结果表明，在这些区域内的高度突变可能会影响RC HBV DNA合成和病毒复制能力，导致严重的肝脏疾病的急性和慢性HBV感染。少

项目成果

Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.

• 发表时间: 2007
• 期刊: Hepatology
• 影响因子: 13.5
• 作者: T. Tatsumi;T. Takehara;Shinjiro Yamaguchi;Akira Sasakawa;R. Sakamori;K. Ohkawa;Keisuke Kohga;A. Uemura;N. Hayashi

Early emergence of entecavir-resistant hepatitis B virus in a patient with hepatitis B virus/human immunodeficiency virus coinfection.

乙型肝炎病毒/人类免疫缺陷病毒双重感染患者早期出现恩替卡韦耐药乙型肝炎病毒。

• 发表时间: 2008
• 期刊: Hepatol Res 38
• 作者: Kanada A;Takehara T;Ohkawa K;et al.
• 通讯作者: et al.

Initial viral response is the most powerful predictor of the emergenceof YMDD mutant virus in chronic hepatitis B patients treated withlamivudine.

在接受拉米夫定治疗的慢性乙型肝炎患者中，初始病毒反应是 YMDD 突变病毒出现的最有力预测指标。

• 发表时间: 2008
• 期刊: Hepatology Research 38
• 作者: Kurashige N;Hiramatsu N;Ohkawa K;et al.
• 通讯作者: et al.

Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in hepatitis B patients treated with lamivudine

初始病毒反应是接受拉米夫定治疗的乙型肝炎患者出现 YMDD 突变病毒的最有力预测因素

• 发表时间: 2006
• 作者: Kurashige;N;Hiramatsu;N;Ohkawa;K;et. al.
• 通讯作者: et. al.

B型急性肝炎と劇症肝炎におけるB型肝炎ウイルスDNA全塩基配列の比較

急性乙型肝炎与暴发性肝炎乙型肝炎病毒DNA全序列比较

• 发表时间: 2007
• 作者: 金田愛衣美、竹原徹郎、大川和良;ら
• 通讯作者: ら