Role and Perturbation of Th17 Cells During HIV Infection

描述（由申请人提供）：Th 17细胞是以产生IL-17为特征的T辅助细胞的新亚群。Th 17细胞在介导对多种病原体的免疫应答中是重要的，并且负责几种自身免疫性疾病的发展。Th 17细胞在HIV感染过程中的作用知之甚少。鉴于它们在微生物防御和促进炎症（特别是在粘膜表面）方面的强大功能，它们在HIV感染期间的紊乱可能对HIV发病机制产生深远影响。在初步研究中，我们提供了大量的证据表明，相当大一部分人Th 17细胞表达CCR 5，对HIV感染易感。我们还发现，在接受治疗的HIV感染受试者的所有阶段，体内Th 17细胞数量都有所减少。值得注意的是，在未经治疗和病毒血症HIV阳性受试者中，Th 17细胞并没有显著降低。这些发现使我们对HIV感染期间Th 17细胞的扰动提出了几个有趣的问题。治疗和非病毒血症HIV+受试者中Th 17细胞水平较低是否是由于慢性免疫激活所致？在感染的病毒血症阶段，是否存在病毒靶向的Th 17细胞亚群？HIV+初治受试者开始治疗后，Th 17细胞数量是否发生变化？是否存在HIV特异性Th 17细胞以及Th 17效应子功能是否在对抗HIV感染中发挥作用？为了回答这些问题，我们提出以下具体目标，以确定：1）在HIV感染受试者中，在治疗开始之前和之后，Th 17细胞的变化及其与其他T细胞亚群的关系，2）可以解释在具有不可检测病毒的经治疗的HIV+受试者中较低水平的Th 17细胞的机制，3）HIV+个体中HIV特异性Th 17细胞的存在以及这些细胞是否通过其效应子功能影响HIV复制。总之，这些方法将是非常重要的理解和确定的机制，其中Th 17细胞在HIV感染过程中的调节及其在HIV疾病的发病机制中的潜在作用。从这些提出的目标中获得的知识也可以使我们使用Th 17细胞作为标记物来预测HIV疾病阶段的过程，并开发新的治疗干预措施或疫苗方法，利用HIV感染期间的Th 17亚群。. 公共卫生相关性：该项目旨在了解最近发现的一种称为Th 17细胞的人类T淋巴细胞亚群在HIV感染过程中的作用。Th 17细胞已被证明介导包括几种自身免疫性疾病在内的主要炎症性疾病，并且它们可能有助于HIV疾病的发病机制。从这些研究中获得的知识可能对HIV感染期间调节该淋巴细胞亚群并确定更好的HIV疾病进展预测标志物具有重要意义。

DESCRIPTION (provided by applicant): Th17 cells are a novel subset of T helper cells characterized by the production of IL-17. Th17 cells were shown to be important in mediating immune responses to variety of pathogens and responsible for development of several autoimmune diseases. Little is known about the role of Th17 cells during HIV infection. Given their potent functions both in microbial defense and promoting inflammation, especially at mucosal surfaces, their disturbance during HIV infection could have profound impact on the HIV pathogenesis. In preliminary studies we provide extensive evidence that a sizeable portion of human Th17 cells express CCR5 and are susceptible to HIV infection. We also found that in vivo Th17 cell numbers were reduced in all stages of HIV-infected subjects that were under treatment. Remarkably, Th17 cells were not significantly lower in untreated and viremic HIV positive subjects. These findings have led us to ask several interesting questions on perturbance of Th17 cells during HIV infection. Is the lower level of Th17 cells in treated and non-viremic HIV+ subjects due to chronic immune activation? Are there subsets of Th17 cells that are targeted by virus during viremic stage of the infection? Does Th17 cell numbers change after HIV+ naove subjects start treatment? Are there HIV-specific Th17 cells and do Th17 effector functions play a role against HIV infection? To answer these questions we propose the following specific aims to determine: 1) changes in Th17 cells and their relationship with other T cell subsets, in HIV-infected subjects, before and after initiation of treatment, 2) mechanisms that could explain lower levels of Th17 cells in treated HIV+ subjects with undetectable virus, 3) presence of HIV-specific Th17 cells in HIV+ individuals and whether these cells influence HIV replication through their effector functions. Together these approaches will be highly significant in understanding and identifying the mechanisms by which Th17 cells are regulated during HIV infection and their potential role in pathogenesis of HIV disease. The knowledge gained from these proposed aims may also allow us to use Th17 cells as a marker to predict the course of HIV disease stages and for developing novel therapeutic interventions or vaccine approaches that take advantage of Th17 subset during HIV infection. . PUBLIC HEALTH RELEVANCE: This project is aimed at understanding the role of a recently identified subset of human T lymphocytes called Th17 cells during HIV infection. Th17 cells have been shown to mediate major inflammatory conditions including several autoimmune diseases and they could contribute to pathogenesis of HIV disease. The knowledge gained from these studies may have important implications in regulating this lymphocyte subset during HIV infection and identify better predictive markers for HIV disease progression.