PATHOGENESIS OF HIV PNEUMONIA--THE SIV MODEL

HIV肺炎的发病机制--SIV模型

• 批准号: 2231078
• 负责人: M CHRISTINE ZINK
• 金额: $ 30.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2231078
• 关键词: Macaca; cytokine; disease /disorder model; enzyme linked immunosorbent assay; histochemistry /cytochemistry; interstitial; leukocyte adhesion molecules; lung lavage; macrophage; molecular pathology; opportunistic infections; pathology; polymerase chain reaction; simian AIDSs; viral pneumonia; virus replication

Interstitial pneumonia is a major component of disease in HIV-infected children and adults. SIV infection in macaques provides an excellent model for the disease seen in children because juvenile macaques inoculated with appropriate strains of SIV develop lymphocytic interstitial pneumonia similar to that seen in HIV-infected children. The SIV/macaque model is ideal to study the pathogenetic mechanisms of lentivirus-induced pneumonia because animals can be infected with biologically cloned and molecularly characterized virus strains, they can be evaluated throughout the course of infection, and the course of disease is not confounded by drug treatment. In previous studies, a macrophage-tropic strain of SIV was selected after repeated in vivo passage of SIV in macaques. This macrophage-tropic virus was also pneumovirulent because when inoculated into macaques it caused typical lymphocytic interstitial pneumonia characterized by intense infiltrates of lymphocytes, lymphoblasts, plasma cells and macrophages in the interalveolar septae and perivascular and peribronchial interstitium. Our hypotheses are l) that the development of pneumonia requires a strain of virus that replicates preferentially in pulmonary macrophages, and 2) that virus replication in the lung induces local dysregulation of pulmonary cytokine systems that, in turn, leads to increased expression of cell adhesion molecules and lymphocyte infiltration. The goal of this study is to characterize the host and virus factors which contribute to the development and progression of lentivirus- induced pulmonary disease. The specific aims are l) to characterize the pathobiology of the host pulmonary response to SIV infection, 2) to determine to what extent productive virus replication is associated with the development of disease, 3) to determine whether during infection there is a selection by the lung for a strain of virus that replicates preferentially in alveolar macrophages, and 4) to identify the molecular changes-that are responsible for pneumovirulence. Rhesus macaques will be inoculated with a macrophage-tropic pneumovirulent strain of SIV and examined for the development of pulmonary disease by both bronchoalveolar lavage (BAL) and sequential sacrifice. BAL and tissue samples will be use to identity the infiltrating cells in the lung, to determine what cytokines are produced in the affected lung, to measure the expression of cell adhesion molecules and to measure virus replication and identify virus tropism. In order to understand at the molecular level how the virus induces pulmonary disease, the macrophage-tropic, pneumovirulent strain of SIV will be sequenced and infectious recombinant viruses will be tested to identify the molecular changes that are important for the development of pulmonary disease.

间质性肺炎是HIV感染的疾病的主要组成部分 儿童和成人。猕猴中的SIV感染提供了出色的模型 因为在儿童中看到的疾病是因为接种了少年猕猴 适当的SIV菌株发展出淋巴细胞间质性肺炎 与在感染HIV的儿童中看到的类似。 SIV/猕猴模型是 研究慢病毒诱导的肺炎的致病机制的理想选择 因为动物可以被生物克隆和分子感染 特征性病毒菌株，可以在整个课程中进行评估 感染和疾病的病程不会被药物混淆 治疗。在先前的研究中，SIV的巨噬细胞 - 循环菌株是 在猕猴中重复体内SIV通过后选择。这 巨噬细胞 - 递归病毒也是肺炎的，因为接种时 猕猴引起典型的淋巴细胞间质肺炎 以淋巴细胞，淋巴细胞和血浆的强烈浸润为特征 细胞和巨噬细胞中的肺泡间隔和血管周围的细胞和巨噬细胞 周期间质。我们的假设是l） 肺炎需要一种病毒菌株，以优先复制 肺巨噬细胞和2）病毒在肺中的复制会诱导 肺部细胞因子系统的局部失调，而肺细胞因子系统又导致 细胞粘附分子和淋巴细胞的表达增加 浸润。这项研究的目的是表征宿主和病毒 有助于慢病毒的发展和发展的因素 诱导肺部疾病。具体目的是表征 宿主对SIV感染的肺反应的病理生物学，2） 确定生产病毒复制在多大程度上与 疾病的发展，3）确定在感染期间是否 是通过肺选择复制的病毒菌株 优先在肺泡巨噬细胞中，4）识别分子 变化 - 导致肺炎。恒河猕猴将是 接种了巨噬细胞 - 授予SIV和 检查了两种支气管肺泡的肺部疾病的发展 灌洗（BAL）和顺序牺牲。 BAL和纸巾样品将使用 识别肺中的浸润细胞，以确定什么 细胞因子在受影响的肺中产生，以测量 细胞粘附分子并测量病毒复制并识别 病毒向西。为了在分子水平上了解病毒 诱导肺部疾病，巨噬细胞，巨噬细胞，肺炎菌株 SIV将进行测序，并将测试感染性重组病毒 确定对发展重要的分子变化 肺病。