Clinical significance of HBV mutation

HBV突变的临床意义

• 批准号: 11670540
• 负责人: HASEGAWA Kiyoshi
• 金额: $ 2.18万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670540/
• 关键词: hepatitis B virus; fulminant hepatitis; mutation; 変異; B型肝炎ウィルス; 遺伝子変異

(1) Different antibody response against hepatitis B surface antigen among mice strains transfected with mutant viral DNAPurpose Rapid seroconversion from HBsAg to anti-HBs antibody is seen in most patients with fulminant hepatitis B. It is unclear whether viral mutation or host immune background is responsible for such enhanced host reaction to HBV. To investigate interaction between virus mutation and host immune background, we established a mouse model of hepatitis B using liposome-mediated gene transfer.Methods A mixture of liposomes and full-length viral DNA derived from hepatitis B patients was injected into 3 strains of purebred mice intrahepatically. After injection, hepatitis B surface antigen and antibody in liver and serum were serially measured.Results Three days after transfection, viral transcript and antigen were detected in the liver and serum. Ten days after transfection with wild-type DNA, hepatitis B surface antibody was detectable in 2 of the 3 strains. Mice that did … More not produce antibody after transfection with wild-type DNA produced a high amount of serum antibody against surface antigen when transfected with fulminant hepatitis-associated DNA.Conclusion The present results are consistent with previous clinical observations of rapid HBsAg seroconversion in patients with fulminant hepatitis B. Further studies are needed to determine which mutations are responsible for differences in immunogenicity between HBV strains.(2) Clinical features and viral sequences of various genotypes of hepatitis B virus compared among patients with acute hepatitis BClinical manifestations and viral sequences of core promoter and precore/core region were compared among various genotypes of hepatitis B virus in 25 patients with acute hepatitis. The genotype in patients with acute hepatitis was distributed differently from that among chronic hepatitis patients in Japan, which are predominantly genotypes B and C. Of 25 patients with acute hepatitis, 14 had genotype A, 5 genotype B and 6 genotype C. Serum total bilirubin levels were significantly higher in patients with genotype A than in those with genotype C. Prothrombin time was shorter in patients with genotype B than those with genotype A or C.Total bilirubin was lower in patients with short duration of acute hepatitis. The serum ALT value remained above 1000 IU/L for over 10 days in 79% of patients with genotype A. This prolonged duration of hepatitis in patients with genotype A may contribute to hyperbilirubinemia. Sequence analysis revealed no difference in the number of mutations in precore/core regions among the three genotypes. Although the double mutation, A-T and G-A at 1762 and 1764, respectively, was found in 2 patients each with genotype A and C, these mutations were not related to the HBeAg/HBeAb phenotype. Two of 7 patients with thymidine at 1858 also had a G to A mutation at 1896. Thus, the difference in the genotype little influenced the HBeAg/HBeAb phenotype in acute hepatitis patients. Understanding the viral genotypes in acute HBV infection may be valuable in predicting the clinical course of acute hepatitis B. Less

(1)转染突变病毒DNA的小鼠品系对乙型肝炎表面抗原的不同抗体反应目的在大多数暴发性乙型肝炎患者中观察到从HBsAg到抗HBs抗体的快速血清转换。目前尚不清楚是否是病毒突变或宿主免疫背景导致宿主对HBV的这种增强反应。为了研究病毒突变与宿主免疫背景之间的相互作用，我们利用脂质体介导的基因转移建立了乙型肝炎小鼠模型。方法将脂质体和乙型肝炎患者全长病毒DNA的混合物注射到3个纯种小鼠的肝内。注射后连续测定肝脏和血清中的乙型肝炎表面抗原和抗体。结果转染三天后，肝脏和血清中检测到病毒转录本和抗原。转染野生型 DNA 10 天后，在 3 个菌株中的 2 个菌株中可检测到乙型肝炎表面抗体。转染野生型 DNA 后不产生抗体的小鼠，在转染暴发性肝炎相关 DNA 时，产生了大量针对表面抗原的血清抗体。 结论 目前的结果与之前暴发性乙型肝炎患者快速 HBsAg 血清转换的临床观察结果一致。需要进一步研究来确定哪些突变导致不同类型之间的免疫原性差异。 (2)急性乙型肝炎患者临床特征及各基因型乙型肝炎病毒病毒序列比较比较25例急性乙型肝炎患者的临床表现及核心启动子和前核心/核心区病毒序列。日本急性肝炎患者基因型分布与慢性肝炎患者不同，以B、C基因型为主。25例急性肝炎患者中，A基因型14例，B基因型5例，C基因型6例。A基因型患者血清总胆红素水平明显高于C基因型患者，B基因型患者凝血酶原时间较短。 急性肝炎病程短的患者总胆红素较低。 79%的A基因型患者血清ALT值在10天以上保持在1000 IU/L以上。A基因型患者肝炎持续时间延长可能导致高胆红素血症。序列分析显示三种基因型之间前核心/核心区域的突变数量没有差异。尽管在 2 名基因型 A 和 C 的患者中分别发现了 1762 年和 1764 年的双突变 A-T 和 G-A，但这些突变与 HBeAg/HBeAb 表型无关。 1858 年出现胸苷的 7 名患者中，有 2 名在 1896 年也出现 G 突变为 A。因此，基因型差异对急性肝炎患者的 HBeAg/HBeAb 表型影响不大。了解急性乙型肝炎病毒感染的病毒基因型可能有助于预测急性乙型肝炎的临床病程。 更少

项目成果

Hasegawa K, Joh R, et al.: "Different antibody response against hepatitis B surface antigen among with strains transfected with mutait viral DNA"Journal of Gastroenterology. 37. 1035-1041 (2002)

Hasekawa K、Joh R 等人：“用突变病毒 DNA 转染的菌株对乙型肝炎表面抗原的不同抗体反应”胃肠病学杂志。

Joh R, Hasegawa K, Torii N, Ogawa M, Kanai N, Naritomi T, Ishikawa K, lizuka A, Shizuma T, Hashimoto E, Hayashi N.: "Repeated jaundice due to YMDD mutant in a patient with prolonged lamivudine therapy for chronic hepatitis B under prednisolone treatment f

Joh R、Hasekawa K、Torii N、Okawa M、Kanai N、Naritomi T、Ishikawa K、lizuka A、Shizuma T、Hashimoto E、Hayashi N.：“慢性拉米夫定长期治疗患者因 YMDD 突变体导致反复黄疸

Kanai K, Hasegawa K, Ogawa M, Naritomi T, Hayashi N.: "Lamivudine treatment for acute exacerbation of hepatitis B in immunosuppressive therapy"Hepatol Res. 22. 223-230 (2002)

Kanai K、长谷川 K、小川 M、成富 T、林 N.：“拉米夫定治疗免疫抑制治疗中乙型肝炎急性加重”Hepatol Res。

Torii N, Hasegawa K, Joh R, Hayashi N: "Configuration and replicative competence of hepatitis B virus DNA in peripheral blood mononuclear cells from chronic hepatitis B patients and patients who have recovered from acute self-limited hepatitis"Hepatol Res

Torii N、Hasekawa K、Joh R、Hayashi N：“慢性乙型肝炎患者和急性自限性肝炎康复者外周血单核细胞中乙型肝炎病毒 DNA 的配置和复制能力”Hepatol Res

Torii N, Hasegawa K, et al.: "Effectiveness and long-term outcome of laminudine therapy for acute hepatitis B"Hepatology Research. 24. 34-41 (2002)

Torii N、Hasekawa K 等人：“拉米米定治疗急性乙型肝炎的有效性和长期结果”肝病学研究。