PROGRESSIVE IMPAIRMENT OF LUNG IMMUNITY IN HIV INFECTION

描述（改编自申请人摘要）：大多数患者 艾滋病毒感染在某些时候会有感染性肺部并发症 在他们的疾病过程中。 然而，这些通常是一个晚 HIV感染的表现，直到CD 4计数下降良好才出现 低于500个细胞/μ l，经常低于200个细胞/μ l。 hiv感染患者 经常有CD 8+细胞毒性T淋巴细胞（CTL）的积累， 早期出现并持续到晚期的肺泡腔 当它们被CD 8+抑制细胞取代时，疾病进程。 这 这种转变预示着艾滋病晚期的快速发展， 与肺部感染的发病率增加有关。 的 改变CD 8+群体可以反映表型从CTL到 抑制细胞的影响下的细胞因子和细胞在 肺泡腔，抑制细胞群的扩张，或 CTL. 这些变化中的任何一个都可能是由艾滋病毒本身或协同作用介导的 与其他有机体的结合提出了一种有趣的可能性， 感染本身可以诱导CTL向抑制细胞转变 在肺泡空间。 对于这一提议，他们假设， 肺部环境的根本性变化导致了艾滋病的定义 当CD 8 + CTL被CD 8+抑制因子取代时，发生肺部感染 细胞 他们建议使用体外细胞培养技术来解决这一假设。 结核分枝杆菌感染模型。 他们推测， 转换是由细胞因子、细胞、HIV和 肺泡腔内的传染性微生物。 在这份报告中，他们将1。 检查不同时间患者肺泡细胞免疫功能的变化 HIV感染的阶段与细胞因子分泌和 诱导细胞免疫应答，2. 确定这些更改是否 通过CTL凋亡介导CD 8 + CTL向抑制细胞的转换， 抑制细胞的扩增或直接表型转换的诱导 从一种细胞类型到另一种，3. 确定是否从CD 8 + CTL切换 肺泡腔中的CD 8+抑制细胞削弱了杀伤能力 结核分枝杆菌，和4. 确定是否存在分枝杆菌 结核病可诱导CD 8 + CTL向CD 8+抑制细胞转换 通过改变肺泡巨噬细胞和T细胞功能，诱导 CD 8+抑制细胞扩增，诱导CD 8 + CTL凋亡，和/或 HIV表达的上调。 理解背后的机制 HIV感染者肺泡腔的改变 疾病将大大有助于我们了解晚期艾滋病毒 感染及其伴随肺部发病率增加， 提供新的基于免疫的治疗策略的建议。

DESCRIPTION (Adapted from the Applicant's Abstract): Most patients with HIV infection will have an infectious pulmonary complication at some point during the course of their disease. However, these are usually a late manifestation of HIV infection, not appearing until CD4 counts fall well below 500 cells/ul and often below 200 cells/ul. HIV-infected patients frequently have an accumulation of CD8+ cytotoxic T lymphocytes (CTL) in the alveolar space which appears early and persists until late in their disease course when they are replaced by CD8+ suppressor cells. This switch heralds the rapid progression of end stage HIV disease and is associated with an increased incidence of pulmonary infections. The changing CD8+ population could reflect a shift in phenotype from CTL to suppressor cells under the influence of cytokines and cells in the alveolar space, expansion of the suppressor cell population, or loss of CTL. Any of these changes may be mediated by HIV itself or in concert with other organisms raising the intriguing possibility that pulmonary infections themselves can induce the switch from CTL to suppressor cells in the alveolar space. For this proposal they hypothesize that the fundamental change in the lung environment which leads to an AIDS defining pulmonary infection occurs when CD8+ CTL are replaced by CD8+ suppressor cells. They propose to address this hypothesis using an in vitro Mycobacterium tuberculosis infection model. They speculate that the switch is caused by a complex interplay between cytokines, cells, HIV and infectious organisms in the alveolar space. In this proposal they will 1. Examine changes in alveolar cell immune function in patients at different stages of HIV infection with regards to cytokine secretion and the induction of cellular immune responses, 2. Determine if these changes mediate the CD8+ CTL to suppressor cell switch through apoptosis of CTL, expansion of suppressor cells, or induction of a direct phenotypic switch from one cell type to the other, 3. Determine if the switch from CD8+ CTL CD8+ suppressor cells in the alveolar space impairs the ability to kill Mycobacterium tuberculosis, and 4. Determine if Mycobacterium tuberculosis can induce the CD8+ CTL to CD8+ suppressor cell switch through alteration of alveolar macrophage and T cell function, induction of CD8+ suppressor cell expansion, induction of CD8+ CTL apoptosis, and/or upregulation of HIV expression. Understanding mechanisms behind the change in the alveolar compartment in HIV-infected patients with advanced disease will contribute substantially to our understanding about late HIV infection and its attendant increase in pulmonary morbidity as well as offer suggestions on novel immune based therapeutic strategies.