HBV AND HCV IN ALCOHOLICS

酗酒者中的乙型肝炎病毒和丙型肝炎病毒

• 批准号: 2607592
• 负责人: Jack R Wands
• 金额: $ 28.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2607592
• 关键词: cytotoxic T lymphocyte; drug abuse; ethanol; gene expression; hepatitis B; hepatitis B antigens; hepatitis B virus group; hepatitis C; hepatitis C virus; histology; host organism interaction; immunity; immunization; laboratory mouse; molecular pathology; polymerase chain reaction; polynucleotides; virus genetics; virus protein

DESCRIPTION (Adapted from the Investigator's Abstract): It has become increasingly apparent using molecular techniques such as polymerase chain reaction (PCR) amplification of hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes in serum or liver that low level persistent viral infection is a major problem in alcoholics with liver disease. There is recent evidence to suggest that chronic ethanol abuse in the setting of HBV and HCV infection promotes the deterioration of the liver disease and increases the risk for development of hepatocellular carcinoma. Thus, it is important to understand the effects of ethanol on the host cellular and humoral immune response to HBV and HCV that may allow for persistent viral infection to occur. This proposal will focus on molecular genetic techniques designed to induce a host immune response to viral structural proteins. We anticipate that such approaches may eventually be used to design antiviral agents that reduce or terminate viral replication in the liver and therefore have clinical applications for the alcoholic. Our aims are as follows: (1) Explore the use of polynucleotide based immunization to generate humoral and cellular immune responses in mice to the highly conserved HCV core protein and study the effects of ethanol on antiviral immune responses. (2) Evaluate the effect of ethanol on cellular and humoral immune responses to HBV large (LBHs) and middle (MHBs) envelope and core proteins as generated by DNA immunization. (3) Study the antiviral effects of HBV dominate negative core mutant constructs used as "intracellular immunogens" to inhibit HBV replication and examine the role of ethanol on intrahepatic viral gene expression in vivo. Indeed, it has not, heretofore, been possible to study cellular immune responses in vivo to HCV and HBV structural proteins with respect to any alcohol effects, since there was no method available to generate viral specific CTL activity in an animal model system. Our preliminary data suggests that polynucleotide based immunization will induce strong cellular immunity to HCV and HBV that may have antiviral activity. These investigations will allow us to assess ethanol effects on such cellular immune responses which will contribute to a better understanding of the pathogenesis of persistent viral infection in the alcoholic with liver disease.

描述（改编自研究者摘要）：它已成为 使用分子技术如聚合酶链 B肝炎病毒（HBV）和丙型肝炎病毒的PCR扩增 血清或肝脏中的HCV基因组， 感染是患有肝病的酗酒者的主要问题。 有 最近的证据表明，慢性乙醇滥用的HBV背景下， 并且HCV感染促进肝病的恶化， 增加了肝细胞癌发展的风险。 照经上所 重要的是要了解乙醇对宿主细胞的影响， 对HBV和HCV体液免疫应答可能导致持续性病毒感染 感染发生。 这项建议将集中在分子遗传学 设计用于诱导宿主对病毒结构的免疫应答的技术 proteins. 我们预计，这种方法最终可能会被用于 设计抗病毒药物，减少或终止病毒在体内的复制， 肝脏，因此有临床应用的酒精。 我们的目标 具体如下：（1）探索利用基于多核苷酸的免疫来 在小鼠体内产生体液和细胞免疫应答， 丙型肝炎病毒核心蛋白的保守性，并研究乙醇抗病毒的作用 免疫反应。 (2)评估乙醇对细胞和 对HBV大（LBH）和中（MHB）包膜的体液免疫应答， 核心蛋白是由DNA免疫产生的。 (3)研究抗病毒药物 HBV显性阴性核心突变体构建体用作 “细胞内免疫原”抑制HBV复制和检查的作用 乙醇对体内肝内病毒基因表达的影响。 的确， 迄今为止，还不可能在体内研究细胞免疫应答， HCV和HBV结构蛋白与任何酒精作用有关，因为 没有可用的方法来产生病毒特异性CTL活性， 动物模型系统 我们的初步数据表明多核苷酸 基础免疫将诱导对HCV和HBV的强细胞免疫， 可能具有抗病毒活性。 这些调查将使我们能够评估 乙醇对这种细胞免疫反应的影响， 更好地了解持续性病毒感染的发病机制， 患有肝病的酒鬼