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。来自HCV病程早期研究的越来越多的数据表明，细胞免疫反应是最终结果的关键决定因素；然而，hcv特异性免疫反应在HIV-1感染个体中的作用尚不清楚。最近发展的敏感技术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患者中系统地应用这些方法。本研究旨在探讨共感染个体中hcv特异性细胞免疫反应的特征。在确定该队列中这些反应的广度、幅度和表位特异性后，将与未感染HIV的对照受试者进行比较。此外，这些反应将被纵向跟踪，以确定抗病毒治疗前后的动态，特别是寻找免疫重建的相关因素。最后，将使用基于四聚体的方法对HCV特异性淋巴细胞进行表征。这些研究将为HCV的发病机制提供重要的见解，特别是对于这一临床重要的患者群体。它们还将有助于我们了解疫苗设计和潜在的免疫疗法。

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.