MOLECULAR AND COMPUTER ANALYSIS OF THE HEPATITIS B VIRUS GENOME

乙型肝炎病毒基因组的分子和计算机分析

• 批准号: 3790792
• 负责人: R H MILLER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3790792
• 关键词: Hepadnaviridae; Pan; antiviral antibody; computer assisted sequence analysis; duck hepatitis B virus; genetic manipulation; genetic models; genome; hepatitis B; hepatitis B virus group; hepatitis vaccine; infectious hepatitis; model design /development; mutant; nucleic acid sequence; nucleotides; virus DNA; virus antigen; virus genetics

Hepatitis B virus (HBV) is the prototype member of the hepadnavirus family, which consists of hepatotropic viruses that infect at least six separate species. Infection with HBV causes polymorphic liver diseases including acute or fulminant hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Over 300 million people throughout the world are chronically infected with HBV and are at risk of developing hepatocellular carcinoma, one of the world's most prevalent forms of cancer. Recently, two classes of HBV mutants have been identified. The first is an antigenic variant of the virus surface (S) gene that was found in individuals who had received immunoprophylaxis for hepatitis B. In each case an identical single nucleotide substitution occurred that resulted in a single amino acid change in a loop of the S protein known to be important in neutralization of the virus and in stimulation of protective immunity. The emergence of this S-gene mutant form of HBV raises important questions about the significance of such neutralization escape mutants and the possible effect they may have on the efficacy of existing monoclonal (recombinant) vaccines for hepatitis B. The second HBV variant discovered recently has a single nucleotide substitution int he precore gene that results in the premature termination of this protein. This variant is associated with fulminant hepatitis in several regions of the world. The objectives of this study are to: (1) establish an animal model for the study of S- and precore gene mutants, (2) establish and determine the infectivity titer of a challenge pool of S-gene mutant virus, (3) determine the ability of licensed recombinant hepatitis B vaccines to protect chimpanzees against challenge with the S-gene mutant, (4) modify existing vaccines, if necessary, to increase their protective efficacy against S- gene mutants, and, (5) determine the complete nucleotide sequence of the precore variant.

B型肝炎病毒（HBV）是嗜肝DNA病毒家族的原型成员， 它由嗜肝病毒组成， 物种 HBV感染可导致多态性肝病，包括 急性或暴发性肝炎、慢性肝炎、肝硬化，以及 肝细胞癌 全世界有3亿多人 慢性感染HBV并有发生肝细胞癌的风险 癌症是世界上最常见的癌症之一。 最近， 已经鉴定了两类HBV突变体。 第一种是抗原 病毒表面（S）基因的变体，在患有 接受了B型肝炎的免疫预防。 在每种情况下， 发生单核苷酸取代，导致单个氨基 已知S蛋白环中的酸性变化在 中和病毒和刺激保护性免疫。 的 这种HBV S基因突变形式的出现提出了重要的问题 关于这种中和逃逸突变体的意义， 它们可能对现有单克隆抗体的疗效产生的影响 用于B型肝炎的（重组）疫苗。 发现的第二个HBV变异体 最近在前C基因中有一个单核苷酸取代， 导致这种蛋白质的提前终止。 该变型 与世界上几个地区的暴发性肝炎有关。 的 本研究的目的是：（1）建立一种动物模型， S-和前C基因突变体的研究，（2）建立和确定 S-基因突变病毒攻击池的感染性滴度，（3）确定 已获许可的重组B型肝炎疫苗的保护能力 黑猩猩对抗S基因突变体的挑战，（4）修改现有的 疫苗，如有必要，以提高其对S- 基因突变体，和，（5）确定完整的核苷酸序列的基因突变体， 前核心变体