Mechanisms of effective adaptive immunity in HCV treatment

丙型肝炎病毒（HCV）感染是导致肝脏相关的发病率和死亡率的主要原因， 美国，由于HCV相关的肝硬化和肝癌死亡人数不断增加 预计在未来20年。自发清除是感染的最佳结局，但这 仅发生在约15 - 45%的患者中。该项目的目标是确定 治疗介导的HCV感染清除中有效的适应性免疫机制。似乎 明确适应性应答，特别是CD8 * 细胞毒性T淋巴细胞（CTL）应答，是必需的， 但不足以清除HCV。例如，对抗病毒治疗有反应的受试者， 抗病毒CTL的频率比无应答者高，但接种前CTL不足以清除 慢性HCV感染此外，在急性感染中，不能建立有效的CTL应答。 缺乏CD4 * T细胞的帮助。我们推测，CD4 * T细胞、干扰素-α IFN α和利巴韦林对CD8 + T细胞的应答在抗原呈递细胞水平上是相关的。 （APC）。 我们假设IFN α和利巴韦林部分通过影响HCV的表达而促进HCV的清除。 通过对APC和先天免疫缺陷细胞的影响介导的适应性免疫应答的质量 免疫系统，包括NK细胞（在项目1中评估）。在这个项目的实验中， 我们将使用来自一组患者的外周血和肝活检标本来阐明这一假设。 回顾性病例对照研究和一项前瞻性研究， HCV感染。我们希望确定抗HCV治疗的成功反应是否 感染与：（1）CD4+的多功能性和成熟表型增强， CD8 * T细胞;（2）改善的DC功能和减少的T调节机制（例如， 诱导T-E1、吲哚胺-2，3-双加氧酶、PD-1等）;和/或（3）高滴度的总抗E1/E2 抗HCV抗体或抗HCV中和抗体。考虑到这些事件之间的时间关系 参数和对治疗的反应，我们也许能够确定哪些可能是因果关系。 结合项目2（先天免疫）的实验来看，我们还将能够 更好地了解先天免疫和获得性免疫在HCV治疗反应中的相互作用。

Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States, with an increasing number of deaths due to HCV-associated cirrhosis and liver cancer predicted over the next two decades. Spontaneous clearance is the best outcome of infection, but this occurs in only approximately 15-45% of patients. The goal of this project is to determine the mechanisms of effective adaptive immunity in treatment-mediated clearance of HCV infection. It seems clear that adapfive responses, particulariy CD8* cytotoxic T lymphocyte (CTL) responses, are necessary but not sufficient for HCV clearance. Subjects who respond to antiviral treatment, for example, have a higher frequency of antiviral CTL than do non-responders, but pre-exisfing CTL are insufficient to clear chronic HCV infection. Furthermore, in acute infecfion, effective CTL responses cannot be established in the absence of CD4* T cell help. We speculate that the contributions of CD4* T cells, interferon-a (IFNa), and ribavirin to CDS* T cell responses are linked at the level of the antigen-presenfing cell (APC). We hypothesize that IFNa and ribavirin contribute to HCV clearance in part via an infiuence on the quality of adaptive immune responses that is mediated by effects on APCs and cells of the innate immune system, including NK cells (evaluated in Project 1). In the experiments of this project, this hypothesis will be addressed using specimens of peripheral blood and liver biopsies from pafients in a retrospecfive case-control study and a prospective study of response to standard-of-care treatment of HCV infection. We wish to determine whether a successful response to antiviral treatment for HCV infecfion is related to: (1) enhancement of the polyfuncfionality and maturafion phenotype of CD4'' and CD8* T cells; (2) improved DC function and decreased induction of T regulatory mechanisms (e.g., inducfion of T-regs, indoleamine-2,3-dioxygenase, PD-1, etc); and/ or (3) high titers of total anti-E1/E2 anfibodies or of neutralizing antibodies against HCV. Given the temporal relationship between these parameters and the response to treatment, we may be able to ascertain which are likely to be causal. Viewed in conjunction with the experiments of Project 2 (on innate immunity), we will also be able to better understand the interplay between innate and adaptive immunity in treatment response to HCV.