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（改编自应用程序）。 宿主和病毒因素， 预测慢性丙型肝炎患者的肝脏疾病进展 没有很好的定义。 HCV感染在大约80%的病例中变成慢性， 并且在大约20年的时间里， %的慢性感染者。 酒精等宿主因素 使用，年龄和性别是导致进展的危险因素。 丙型肝炎 然而，对宿主-病毒相互作用的研究一直是 由于疾病的长期自然史和缺乏良好的， 保存的血清库，用于纵向地形分析。 实验 项目3中概述的目的是确定HCV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因子 慢性丙型肝炎的临床表现 三个具体目标将是 处理。 (1)慢性丙型肝炎的病因有哪些？ 阿拉斯加原住民（ANA）队列，并评估流行病学的影响 以及宿主因素对病毒复制和疾病结果的影响。(2)确定 进展性肝病患者HCV病毒血症的纵向模式 损伤和基因型匹配的疾病非进展受试者。（三） 确定HCV准种遗传多样性随时间的变化率， 发生进行性肝损伤的受试者和基因型匹配的受试者 他们是疾病非进展者，并研究特定的 病毒突变对受感染的宿主可能是保护性的，也可能是有害的。 这些研究于1996年开始，涉及110名受试者， 对来自500多名受试者的储存血清标本进行了研究， ANA队列。在所有病例中，HCV基因型和病毒血症状态，首次和 最新的阳性样本已经确定。 在某些情况下， 足够的样本储存和当前肝活检结果，纵向 定量病毒血症谱和准种突变模式超过5-20 年将使用分子技术的特点。 一个广泛 临床和人口统计数据库正在建设中， 分析宿主-病毒关系对慢性病毒性肝炎进展的重要性 肝炎 C. 数据分析将与 安克雷奇北极调查计划（AIP）的调查人员和 美国疾病控制和预防中心病毒性肝炎分支 以及阿拉斯加土著医疗中心（ANMC）的病毒性肝炎项目。