Functional attributes of CD8+ T cells in recovery of hepatitis C virus infection

描述(由申请人提供)： PI：雨果·R·罗森，医学博士/丹佛，弗吉尼亚州，荣誉审查补助金：CD8+T细胞在丙型肝炎病毒感染恢复中的功能属性全世界大约有2亿人患有慢性丙型肝炎病毒感染。高达80%的感染者感染了丙型肝炎病毒。仅在美国，未来10-20年的直接医疗成本预计将超过100亿美元，社会总成本将翻一番。丙型肝炎病毒是导致肝癌和肝移植的主要病因。尽管新的治疗方法提高了持续应答率，但很大比例(~50%)的患者对抗病毒治疗无效或出现显著的药物毒性，因此仍面临疾病进展的风险。需要了解丙型肝炎病毒与宿主之间的相互作用，以对抗这种病毒并开发改进的治疗方法。虽然从感染的早期阶段获得的数据提供了最大的机械性见解，但急性丙型肝炎往往没有被识别出来，因为症状通常很轻微或没有。需要对急性和演变中的丙型肝炎病毒感染进行详细的前瞻性研究，以阐明逃逸突变在丙型肝炎病毒持续存在中的作用，以及确定控制病毒进化的免疫学和病毒学因素。特别是，仔细分析这些因素对于设计任何有效的基于T细胞的治疗将是至关重要的。 公共卫生相关性： 项目简介丙型肝炎病毒(丙型肝炎病毒)在退伍军人中的重要性怎么强调都不为过：虽然丙型肝炎病毒在普通人群中的发病率约为2%，但据报道，退伍军人中丙型肝炎病毒的发病率在18%-35%之间。对其重要性的日益认识反映在退伍军人事务部的任务中，即对所有有患丙型肝炎风险的退伍军人进行丙型肝炎病毒检测。疾病模型预测，在本世纪的头20年，丙型肝炎病毒相关的发病率和死亡率将激增，这一点现在正在实现。丙型肝炎病毒相关的并发症，包括肝硬变、肝细胞癌和需要肝移植，在退伍军人事务部内具有巨大的医疗保健和经济影响。此外，尽管抗病毒治疗的疗效有所提高，但研究表明，由于一些重要的障碍，退伍军人管理局诊所只有一小部分患者曾接受过抗病毒治疗。因此，加强对免疫系统如何控制或更经常地无法控制丙型肝炎病毒感染的了解，对于退伍军人管理局人群来说是迫切需要的。书目精选：Fimmel CJ.与丙型肝炎病毒作斗争。美国胃肠病杂志2000；95：582-583。戴维斯·GL、奥尔布赖特·杰、库克·SF、罗森博格·DM。预测美国慢性丙型肝炎的未来并发症。肝脏移植。2003年4月；9(4)：331-8 Leykum LK，El-Serag HB，Cornell J，Papadoulos KP。丙型肝炎退伍军人中肝细胞癌的筛查：疾病分期、接受的治疗和生存期。临床胃肠激素，肝醇。2007年4月；5(4)：508-12。ePub 2007-3-26 Ho SB，Groessl E，DollarHide A，Robinson S，Kravetz D，Dieperink E.退伍军人慢性丙型肝炎的管理：综合护理模式的潜力。我是J·胃肠毒素。2008年7月；103(7)：1810-23。

DESCRIPTION (provided by applicant): PI: Hugo R. Rosen, MD/ Denver VA Title of Merit Review Grant: Functional attributes of CD8+ T cells in recovery of hepatitis C virus infection Approximately 200 million throughout the world have chronic HCV infection. HCV persists in up to 80% of people infected. In the US alone, the burden over the next 10- 20 years is expected to reach over $10 billion in direct medical costs and double this in overall societal costs. HCV is a leading etiology of liver cancer and cause for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (~50%) fail to respond to antiviral treatment or develop significant drug toxicity, thus remaining at risk for disease progression. An understanding of HCV-host interactions is required to combat this virus and to develop improved therapies. Although data derived from the earliest stages of infection provide the greatest mechanistic insights, acute HCV is often unrecognized because symptoms are usually mild or absent. Detailed prospective studies of acute and evolving HCV infection are required to delineate the role of escape mutations in HCV persistence, as well as to define the immunological and virological factors governing viral evolution. In particular, careful dissection of these factors will be critical to the design of any effective T-cell based therapy. PUBLIC HEALTH RELEVANCE: Project Narrative The importance of hepatitis C virus (HCV) in the VA population cannot be overstated: whereas the incidence of HCV in the general population is approximately 2%, the point prevalence among VA patients has been reported to range from 18%-35%. The growing awareness of its importance is reflected in the mandate by the Department of Veterans Affairs to perform HCV testing on all veterans at risk for the disease. Disease modeling predicted a surge in HCV-related morbidity and mortality over the first two decades of this century, which is now being realized. HCV-related complications including cirrhosis, hepatocellular (liver cell) cancer and need for liver transplantation, have tremendous health care and economic ramifications within the VA. Moreover, despite the improving efficacy of antiviral therapies, studies indicate that only a minority of patients in VA clinics have ever received antiviral therapy because of a number of important barriers. Thus, enhanced understanding of how the immune system controls, or more frequently fails to control, HCV infection is sorely required for the VA population. Selected Bibliography: Fimmel CJ. Doing battle with HCV. Am J Gastroenterol 2000; 95: 582-583. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003 Apr;9(4):331-8 Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP. Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol. 2007 Apr;5(4):508- 12. Epub 2007 Mar 26 Ho SB, Groessl E, Dollarhide A, Robinson S, Kravetz D, Dieperink E. Management of chronic hepatitis C in veterans: the potential of integrated care models. Am J Gastroenterol. 2008 Jul;103(7):1810-23.