Bay Area Hepatitis C Cooperative Research Center

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染是美国与肝脏相关的发病率和死亡率的主要原因。虽然一些感染者的病毒会自发清除，而目前的治疗方案在另一些人中产生了持续的病毒学应答，但治疗失败的频率仍然高得令人无法接受。为了更好地了解免疫反应对病毒清除的贡献，我们建议建立湾区丙型肝炎合作研究中心。该中心的目标是在慢性感染的背景下定义针对丙型肝炎病毒的先天和获得性免疫反应的生物学，了解这些反应是如何通过治疗调节的，并辨别免疫反应的哪些参数与有效的抗病毒治疗反应相关(或可能预测)。该中心将组建一支强大的多学科团队，由旧金山湾区多个地点的免疫学家和临床研究人员组成，其中包括与加州大学旧金山分校(UCSF)(旧金山总医院、加州大学医疗中心和旧金山退伍军人事务医疗中心)以及加州太平洋医学中心、血液系统研究所和北加州凯撒永久医疗中心(KP)有关的三个不同地点。临床流行病学核心(由KP研究部的Michele Manos博士和加州大学旧金山分校的Norah Terrault博士领导)将开发和管理(A)对标准治疗有反应或无反应的200名受试者的回溯性病例对照队列，以及(B)在开始治疗之前和之后将进行跟踪的未接受治疗的受试者的预期队列。在项目1(由加州大学旧金山分校的James Ryan和Lewis Lanier博士领导)中，将研究先天免疫对治疗反应的贡献。同时，使用相同的一组患者样本。项目2(由加州大学旧金山分校的Dennis Hartigan-O‘Connor博士和Joseph McCune博士领导)将分析适应性T和B细胞对丙型肝炎病毒的反应的作用。对这两个项目中获得的数据进行协调分析，将允许对离散假设进行测试，这些假设说明了固有系统和适应性系统之间的相互作用。该中心的活动将通过一个行政核心组织，由国际和平协会(McCune博士)领导。我们预计，该中心的努力将提供数据，在短期内为治疗决策提供参考，并在长期内为开发更好和更普遍适用的慢性丙型肝炎治疗方法做出贡献。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States. Although spontaneous clearance of virus occurs in some who are infected and current treatment regimens result in sustained virologic response in others, there remains an unacceptably high frequency of treatment failure. To better understand the contribution of the immune response to viral clearance, we propose the creation of a Bay Area Hepatitis C Cooperative Research Center. The goals of this Center are to define the biology of the innate and adaptive immune responses to HCV in the setting of chronic infection, to understand how these responses are modulated by treatment, and to discern which parameters of the immune response are associated with (and possibly predictive of) an effective antiviral response to therapy. The Center will assemble a strong multidisciplinary team comprised of immunologists and clinical investigators at multiple sites in the San Francisco Bay Area, including three different sites associated with the University of California at San Francisco (UCSF) (San Francisco General Hospital, UC Medical Center, and the San Francisco Veterans Affairs Medical Center) as well as with the California Pacific Medical Center, the Blood Systems Research Institute, and Kaiser Permanente (KP) of Northern California. A Clinical Epidemiology Core (led by Drs. Michele Manos of KP Division of Research and Norah Terrault of UCSF) will develop and manage (a) a retrospective case-control cohort of 200 subjects who did or did not respond to standard-of-care therapy, and (b) a prospective cohort of treatment-naive subjects who will be followed before and after the initiation of therapy. In Project 1 (led by Drs. James Ryan and Lewis Lanier of UCSF), the contribution of innate immunity to treatment response will be studied. Concomitantly, and using the same set of patient samples. Project 2 (led by Drs. Dennis Hartigan- O'Connor and Joseph McCune of UCSF) will analyze the role of adaptive T and B cell responses against HCV. Coordinated analyses of data obtained in both Projects will permit tests of discrete hypotheses that speak to interactions between the innate and adaptive systems. The activities of the Center will be organized through an Administrative Core, directed by the PI (Dr. McCune). We anticipate that the efforts of this Center will provide data that can inform treatment decisions in the short term and contribute to development of better and more generally applicable therapies for chronic HCV disease in the longer term.