Mechanisms of effective adaptive immunity in HCV treatment

丙型肝炎病毒(丙型肝炎病毒)感染是与肝脏相关的发病率和死亡率的主要原因。 美国，死于丙型肝炎相关性肝硬变和肝癌的人数不断增加 预测在未来20年内。自然清除是感染的最好结果，但这 仅在大约15%-45%的患者中发生。该项目的目标是确定 有效适应性免疫在治疗介导的丙型肝炎病毒感染清除中的机制。似乎 明确适应五种反应，特别是CD8*细胞毒性T淋巴细胞(CTL)反应是必要的 但不足以清除丙型肝炎病毒。例如，对抗病毒治疗有反应的受试者有 抗病毒CTL的频率高于无应答者，但预先存在的CTL不足以清除 慢性丙型肝炎病毒感染。此外，在急性感染中，有效的CTL反应不能建立在 CD4*T细胞的缺失对此有帮助。我们推测，CD4*T细胞、干扰素-a的作用 (IFNA)和利巴韦林对CDS*T细胞的反应在抗原提呈细胞水平上相连 (APC)。 我们推测IFNA和利巴韦林有助于丙型肝炎病毒的清除，部分是通过影响 通过对APC和先天细胞的影响而介导的获得性免疫反应的质量 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，这个 假说将使用一个患者的外周血液和肝脏活检样本来解决。 慢性阻塞性肺疾病标准治疗疗效的病例对照研究和前瞻性研究 丙型肝炎病毒感染。我们希望确定丙型肝炎病毒抗病毒治疗的成功应答 感染与：(1)CD_4~+和CD_4~+细胞的多功能性和成熟表型增强有关。 CD8*T细胞；(2)改善DC功能并减少T调节机制的诱导(例如， 诱导T-Regs、吲哚-2，3-双加氧酶、PD-1等)；和/或(3)高滴度的总抗-E1/E2 抗丙型肝炎病毒抗体或中和抗体。考虑到它们之间的时间关系 参数和对治疗的反应，我们可能能够确定哪些可能是因果关系。 结合项目2(关于先天免疫)的实验来看，我们也将能够 更好地理解先天免疫和获得性免疫在丙型肝炎病毒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.