MOLECULAR AND COMPUTER ANALYSIS OF THE HEPATITIS B VIRUS GENOME

乙肝病毒(HBV)是肝炎病毒家族的原型成员， 它由嗜肝病毒组成，感染至少六个独立的 物种。感染乙肝病毒会导致多种肝病，包括 急性或暴发性肝炎、慢性肝炎、肝硬变和 肝细胞癌。全世界有超过3亿人 长期感染乙肝病毒，并有发展为肝细胞癌的风险 癌症，世界上最常见的癌症之一。最近， 目前已鉴定出两类乙肝病毒突变株。第一种是抗原性 病毒表面(S)基因的变种，发现于患有 接受了乙肝的免疫预防，在每个病例中 发生了单核苷酸替换，从而产生了单个氨基 已知的S蛋白环中的酸变化在 中和病毒和刺激保护性免疫。这个 这种S基因突变的乙肝病毒的出现提出了重要的问题 关于这种中和逃逸突变的意义以及 它们可能对现有单抗的效力产生影响 (重组)乙肝疫苗发现第二个乙肝病毒变异株 最近在前C基因上有一个单核苷酸替换 导致这种蛋白质的提前终止。这个变种是 与世界上几个地区的暴发性肝炎有关。这个 本研究的目的是：(1)建立大鼠脑缺血再灌注损伤动物模型 S和前C基因突变体的研究，(2)建立和测定 S基因突变病毒攻击池的感染性滴度测定 获得许可的重组乙肝疫苗保护作用的能力 黑猩猩用S基因突变体对抗挑战，(4)修改现有 疫苗，如有必要，以增强对S的保护效果- 基因突变，以及，(5)确定该基因的完整核苷酸序列 前核心变种。

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.