Cell mediated Immunity to HCV in HIV+ Persons

描述（由申请人提供）：丙型肝炎病毒（HCV）感染已成为人类免疫缺陷病毒（HIV-1）感染者发病和死亡的主要原因。越来越多的研究数据表明，在早期的HCV过程中的细胞免疫反应是一个关键的决定因素，最终的结果;然而，在HIV-1感染者的HCV特异性免疫反应的作用尚不清楚。敏感技术的最新发展允许对这种免疫反应进行全面和详细的评估，并且候选人已经开始在合并感染的患者中系统地应用这些方法。该建议旨在描述合并感染个体中HCV特异性细胞免疫应答的特征。在确定该队列中这些应答的宽度、幅度和表位特异性后，将其与未感染HIV的对照受试者进行比较。此外，这些反应将被纵向跟踪，以确定它们在抗病毒治疗前后的动态，特别是找到免疫重建的相关性。最后，将使用基于四聚体的方法表征对HCV具有特异性的淋巴细胞。这些研究将为深入了解HCV的发病机制提供重要的见解，特别是在这一临床重要的患者群体中。它们还将有助于我们理解疫苗设计和潜在的免疫疗法。 该候选人目前正在马萨诸塞州总医院接受传染病临床和研究奖学金培训的第三年，并寻求进一步的实验室和临床研究技能培训，使他能够发展成为一名独立的临床研究者。这些技能对于将这项研究转化为新的免疫疗法至关重要。该计划将在布鲁斯步行者博士的监督下实施，并将涉及实验室研究、数据分析和教学式学习。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection has emerged as a major cause of morbidity and mortality in persons living with human immunodeficiency virus (HIV-1). Growing data from studies early in the course of HCV suggests that the cellular immune response is a crucial determinant of the eventual outcome; however, the role of the HCV-specific immune response in HIV-1 infected individuals is not clear. The recent development of sensitive techniques allows comprehensive and detailed assessment of this immune response, and the candidate has begun systematic application of these methods in co-infected patients. This proposal aims to characterize the HCV-specific cellular immune response in co-infected individuals. After determining the breadth, magnitude, and epitope specificity of these responses within this cohort, they will be compared to control subjects who are not infected with HIV. Moreover, these responses will be followed longitudinally to determine their dynamics before and after antiviral therapies, and in particular to find correlates of immune reconstitution. Finally, the lymphocytes specific against HCV will be characterized using tetramer-based methods. These studies will lend important insight into the pathogenesis of HCV, especially in regards to this clinically important group of patients. They will additionally contribute to our understanding of vaccine designs and potential immune-based therapies. The candidate is currently enrolled in his third year of clinical and research fellowship training in Infectious Diseases at the Massachusetts General Hospital, and seeks further training in both bench and clinical research skills that will allow him to develop into an independent clinical investigator. These skills will be essential to allow translation of this research into novel immunotherapies. This plan will be implemented under the supervision of Dr. Bruce Walker, and will involve bench research, data analysis, and didactic learning.