滤泡辅助性T细胞在艾滋病免疫重建中的机制及临床意义研究

项目名称： 滤泡辅助性T细胞在艾滋病免疫重建中的机制及临床意义研究

项目编号： No.81471577

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈威巍

作者单位： 中国人民解放军总医院

项目金额： 80万元

中文摘要： 高效抗逆转录病毒治疗（HAART）是慢性HIV感染/AIDS最主要的治疗手段，然而仍有20%的患者表现为免疫重建失败，目前尚无有效的治疗方法，其关键在于其发生机制不清。我们前期研究发现，滤泡辅助性T细胞（follicular helper T cells，TFH）在免疫重建失败患者显著低于免疫重建成功者。据此，我们假设免疫重建失败患者的TFH细胞分泌IL-21功能受损，是导致其不能辅助B细胞产生有效的特异性体液免疫应答的主要原因，从而最终推动免疫重建失败的发生。本项目拟通过我们已经建立的HIV-1感染者HAART治疗的长期随访队列，分析TFH细胞频率、重要分子表达水平、功能变化及其与B细胞抗体产生能力和免疫重建的关系；再通过体外功能实验，重点阐明共抑制性分子PD-1/PD-L1在TFH细胞和B细胞相互作用中的关键机制。该研究为今后针对TFH细胞设计新的治疗靶点和疫苗提供新的思路和科学依据。

中文关键词： 艾滋病；滤泡辅助性T细胞；免疫重建；高效抗逆转录病毒治疗

英文摘要： Highly active antiretroviral therapy (HAART) effectively suppresses HIV-1 viral replication, leading to a significant immune recovery and a dramatic reduction in the incidence of AIDS-defining events. However, around 20% of individuals who exhibit stable viral suppression by HAART still fail to achieve sufficient immune reconstitution and are considered as immune non-responders (INRs). These INRs often experience an increased risk of opportunistic infections and shorter life expectancy compared with matched immune responders (IRs), and still lack of efficient treatment in the clinic. The main hinder is that the mechanism of immune pathogenesis in INRs remains unclear. We previously found that the frequency of TFH cells in INRs was significantly lower than that of IRs. Thus, we hypothesize that the up-regulation of PD1/PDL1 may impair TFH cell function, which subsequently may produce inefficient IL-21 and mediate the poor HIV-1-specific B cell responses in INRs as compared with IRs, thus leading to the progression of immune reconstitution failure. We will first study the correlations between the dynamic of TFH cells including frequency, phenotypes and functions and immune reconstitution in HIV-1-infected patients who have experienced long-term HAART. Then, we will confirm above hypothesis in vitro assay. This study will shed new light on the mechanism of TFH cells in the immune reconstitution failure and find a new candidate for immunotherapy in HIV-1-infected INRs.

英文关键词： AIDS;follicular helper T cells;TFH;immune reconstitution;highly active antiretroviral therapy;HAART