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

在HBV感染的细胞中存在三种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能够形成具有感染性的成熟HBV病毒粒子。在这项研究中，我们研究了影响RC HBV DNA合成的HBV突变及其在HBV相关肝脏疾病发病机制中的作用。1)确定乙型慢性肝炎致死性加重患者RC HBV DNA合成增加的HBV突变。我们有一例慢性乙型肝炎患者，病情加重致死性。从加重前（P1）和加重后（P2） 1年的血清样本中获得HBV全长dna，并将其命名为HBV P1和P2菌株。在培养细胞中表达HBV P1和P2菌株时，表达P2的细胞的RC HBV DNA水平高于表达P1的细胞。进一步的详细分析表明，nt 2790从P1到P2的G-to-A突变是导致该患者RC HBV DNA合成增加和随后疾病恶化的可靠突变。2)乙型急慢性肝病患者HBV突变影响RC HBV DNA合成与病情严重程度的关系。到目前为止，三个区域α (nt2817-2936), γ (nt1909-2141)和δ (nt1373-1589)已被证明是在RC HBV DNA合成中起重要作用的顺式作用元件。在本研究中，我们对44例B型慢性肝病患者和15例B型急性肝病患者进行了HBV全长DNA测序分析。α、γ和δ区域的突变程度与疾病严重程度相关。在慢性肝病患者中，肝硬化和肝癌患者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，暴发性肝炎患者α、γ区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，这些区域的高度突变可能会影响RC HBV DNA的合成和病毒的复制能力，从而导致急性和慢性HBV感染的严重肝脏疾病。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.

VIRAL MUTATIONS AFFECTING EFFICACY OF ADEFOVIR DIPIVOXIL THERAPY ADDED TO ONGOING LAMIVUDINE IN CHRONIC HEPATITIS B

病毒突变影响阿德福韦酯联合拉米夫定治疗慢性乙型肝炎的疗效

• 发表时间: 2007
• 作者: 大川和良;ら
• 通讯作者: ら