Bay Area Hepatitis C Cooperative Research Center

描述（由申请人提供）：丙型肝炎病毒（HCV）感染是美国肝脏相关发病率和死亡率的主要原因。尽管在一些感染者中发生病毒的自发清除，并且当前的治疗方案在其他人中导致持续的病毒学应答，但仍然存在不可接受的高频率的治疗失败。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。该中心的目标是定义慢性感染背景下对HCV的先天性和适应性免疫反应的生物学，了解这些反应如何通过治疗进行调节，并识别免疫反应的哪些参数与有效的抗病毒治疗反应相关（并可能预测）。该中心将组建一支强大的多学科团队，由弗朗西斯科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弗朗西斯科分校（UCSF）相关的三个不同地点。（旧金山弗朗西斯科总医院、加州大学医疗中心和旧金山弗朗西斯科退伍军人事务医疗中心）以及与加州太平洋医疗中心、血液系统研究所、和北方加州的Kaiser Permanente（KP）。临床流行病学核心（由KP研究部的Michele Manos博士和UCSF的Norah Terrault博士领导）将开发和管理（a）一个回顾性病例对照队列，包括200例对标准治疗有或无应答的受试者，以及（B）一个前瞻性队列，包括将在治疗开始前后进行随访的初治受试者。在项目1（由UCSF的James Ryan和刘易斯Lanier博士领导）中，将研究先天免疫对治疗反应的贡献。同时使用同一组患者样本。项目2（由加州大学旧金山分校的Dennis Hartigan-奥康纳博士和Joseph McCune博士领导）将分析针对HCV的适应性T和B细胞反应的作用。对这两个项目中获得的数据进行协调分析，将允许对先天系统和适应系统之间相互作用的离散假设进行检验。中心的活动将通过PI（McCune博士）指导的行政核心组织。我们预计，该中心的努力将提供数据，可以在短期内为治疗决策提供信息，并有助于开发更好和更普遍适用的慢性HCV疾病治疗方法。

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.