HCV replication and liver injury in the human host

HCV 在人类宿主中的复制和肝损伤

• 批准号: 6659986
• 负责人: David Richard Gretch
• 金额: $ 21.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6659986
• 关键词: Alaskan Native American; chronic disease /disorder; clinical research; cooperative study; disease /disorder proneness /risk; disease /therapy duration; genetic susceptibility; hepatitis C; hepatitis C virus; host organism interaction; human tissue; liver disorder; longitudinal human study; outcomes research; pathologic process; prognosis; virus genetics; virus load; virus replication

Description (adapted from the application). The host and viral factors that predict progression of liver disease in humans with chronic hepatitis C are not well defined. HCV infection becomes chronic in about 80 percent of cases, and progressive liver disease develops over several decades in about 20 percent of chronically infected individuals. Host factors such as alcohol use, age and gender have been implicated as risk factors for progression of hepatitis C. However, investigation of host-viral interactions has been difficult due to the long natural history of disease and lack of well- preserved serum banks for longitudinal orological analyses. The experiments outlined in Project 3 are designed to determine whether levels of HCV replication (serum HCV RNA titers) and/or genetic variability within the HCV RNA genome are significant predictors of the long-term clinico- pathological outcome of chronic hepatitis C in humans. Three specific aims will be addressed. (1) Define the natural history of chronic hepatitis C in the Alaskan Native American (ANA) cohort, and assess the impact of epidemiological and host factors on viral replication and disease outcome. (2) Determine the longitudinal patterns of HCV viremia in subjects who develop progressive liver injury and in genotype-matched subjects who are disease non-progressors. (3) Determine the rates of HCV quasispecies genetic diversification over time in subjects who develop progressive liver injury and in genotype matched subjects who are disease non-progressors, and investigate the possibility that specific viral mutations may be either protective or detrimental to the infected host. The studies, which were initiated in 1996 on 110 subjects, are presently being conducted on stored serum specimens from over 500 subjects recruited into the ANA cohort. In all cases, HCV genotype and viremia status, date of first and most recent positive specimen, have been determined. In select cases with adequate sample storage and current liver biopsy results, longitudinal quantitative viremia profiles and quasispecies mutation patterns over 5-20 years will be characterized using molecular technologies. An extensive clinical and demographic database is under construction to allow detailed analysis of host-viral relationships important for progression of chronic hepatitis C. Data analyses will be conducted in collaboration with investigators at the Arctic Investigations Program (AIP) in Anchorage and the Viral Hepatitis Branch of the Centers for Disease Control and Prevention (CDC) and the Viral Hepatitis Program at the Alaska Native Medical Center (ANMC).

描述（根据应用程序改编）。 宿主和病毒因素 预测患有慢性丙型肝炎的人类肝病的进展是 定义不当。 HCV感染在约80％的病例中慢性病， 大约20年来，进行性肝病发展了几十年 长期感染的个体百分比。 宿主因素，例如酒精 使用，年龄和性别已被认为是发展的风险因素 乙型肝炎。但是，对宿主病毒相互作用的研究已经 由于疾病的自然历史悠久，缺乏良好 保留的血清库进行纵向口学分析。 实验 项目3中概述的旨在确定HCV的水平是否 复制（血清HCV RNA滴度）和/或HCV内的遗传变异性 RNA基因组是长期临床病理的重要预测指标 人类慢性丙型肝炎的结果。 三个具体目标将是 解决。 （1）定义慢性丙型肝炎的自然史 阿拉斯加原住民（ANA）队列，并评估流行病学的影响 以及有关病毒复制和疾病结局的宿主因素。 （2）确定 发展进展性肝脏的受试者中HCV病毒血症的纵向模式 损伤和基因型匹配的受试者，这些受试者是非疾病的。 （3） 随着时间的流逝，确定HCV准植物遗传多样化的速率 发展进行性肝损伤并在基因型中与受试者相匹配的受试者 谁是非疾病的人，并研究了特定的可能性 病毒突变可能对受感染的宿主有害或有害。 这些研究于1996年启动了110名受试者，目前正在 从500多名受试者的储存的血清标本进行的 安娜队员。在所有情况下，HCV基因型和病毒血症状况，首先的日期以及 最新的阳性标本已被确定。 在某些情况下 足够的样品存储和当前的肝活检结果，纵向 5-20的定量病毒血症概况和准特性突变模式 使用分子技术将表征年度。 广泛 临床和人口统计数据库正在建设中，以详细说明 对宿主 - 病毒关系的分析对于慢性的进展很重要 丙型肝炎。数据分析将与 北极调查计划（AIP）的研究人员在安克雷奇和 疾病控制与预防中心的病毒肝炎分支（CDC） 以及阿拉斯加本地医疗中心（ANMC）的病毒肝炎计划。