HBV AND HCV IN ALCOHOLICS

描述(改编自《调查者摘要》)：它已经成为 使用聚合酶链等分子技术变得越来越明显 乙肝病毒和丙型肝炎的聚合酶链式反应扩增 血清或肝脏中低水平持续病毒的病毒(HCV)基因组 感染是患有肝病的酗酒者的主要问题。的确有 最近的证据表明，慢性酒精滥用在乙肝病毒的背景下 丙型肝炎病毒感染促进肝病恶化， 增加患肝细胞癌的风险。因此，它是 了解乙醇对宿主细胞和 对乙肝病毒和丙型肝炎病毒的体液免疫反应可能允许持续病毒 感染就会发生。这项提案将重点放在分子遗传学上 旨在诱导宿主对病毒结构的免疫反应的技术 蛋白质。我们预计，这种方法最终可能被用于 设计能减少或终止病毒复制的抗病毒药物 因此对酒精者有临床应用价值。我们的目标 具体如下：(1)探索使用基于多核苷酸的免疫来 在小鼠体内产生高度的体液和细胞免疫反应 丙型肝炎病毒核心蛋白的保守及乙醇抗病毒作用的研究 免疫反应。(2)评价乙醇对细胞和细胞的影响 对乙肝病毒大(LBHs)和中(MHBs)包膜的体液免疫应答 DNA免疫产生的核心蛋白。(3)研究抗病毒药物 乙肝病毒控制阴性核心突变结构的作用 “细胞内免疫原”对乙肝病毒复制的抑制作用及检测 乙醇对体内肝内病毒基因表达的影响。事实上，它已经做到了 到目前为止，还不可能研究体内的细胞免疫反应 丙型肝炎病毒和乙肝病毒结构蛋白与酒精的任何影响，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 基础免疫将诱导对丙型肝炎病毒和乙肝病毒的强大细胞免疫 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，这将有助于 更好地了解持续性病毒感染的发病机制 患有肝病的酗酒者。

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.