Role and Perturbation of Th17 Cells During HIV Infection

描述（由申请人提供）：Th17细胞是T辅助细胞的一个新子集，其特征是产生IL-17。Th17细胞被证明在介导多种病原体的免疫反应中起重要作用，并负责几种自身免疫性疾病的发展。人们对Th17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（尤其是粘膜表面）方面的强大功能，它们在HIV感染过程中的紊乱可能对HIV的发病机制产生深远的影响。在初步研究中，我们提供了大量证据，证明相当大一部分人类Th17细胞表达CCR5并易受HIV感染。我们还发现，在接受治疗的hiv感染受试者的所有阶段，体内Th17细胞数量都减少了。值得注意的是，在未经治疗和病毒血症HIV阳性的受试者中，Th17细胞并没有显著降低。这些发现使我们对HIV感染期间Th17细胞的扰动提出了几个有趣的问题。在治疗和非病毒血症HIV+受试者中Th17细胞水平较低是由于慢性免疫激活吗？在感染的病毒血症阶段，是否有Th17细胞亚群被病毒靶向？HIV阳性受试者开始治疗后Th17细胞数量会改变吗？是否存在HIV特异性Th17细胞？ Th17效应功能是否在抗HIV感染中发挥作用？为了回答这些问题，我们提出了以下具体目标来确定：1)在HIV感染者中，在治疗开始前后，Th17细胞的变化及其与其他T细胞亚群的关系；2)在治疗的HIV+患者中，无法检测到病毒的Th17细胞水平较低的机制；3)HIV+个体中HIV特异性Th17细胞的存在，以及这些细胞是否通过其效应功能影响HIV复制。总之，这些方法对于理解和确定Th17细胞在HIV感染过程中受到调节的机制及其在HIV疾病发病机制中的潜在作用具有重要意义。从这些提出的目标中获得的知识也可能使我们能够使用Th17细胞作为标记物来预测HIV疾病阶段的进程，并开发新的治疗干预措施或疫苗方法，利用HIV感染期间的Th17亚群。

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.