Chemokine Dynamics in the HIV-1/SIV Infected Lung

HIV-1/SIV 感染肺中的趋化因子动态

• 批准号: 6784042
• 负责人: Denise E Kirschner
• 金额: $ 51.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784042
• 关键词: Macaca fascicularis; cellular immunity; chemokine; chemotaxis; cytokine; disease /disorder model; enzyme linked immunosorbent assay; gene expression; human immunodeficiency virus 1; immunoregulation; in situ hybridization; leukocyte activation /transformation; lung; lymph; lymph nodes; microarray technology; polymerase chain reaction; simian immunodeficiency virus; virus infection mechanism

DESCRIPTION (provided by applicant): The lung is an extremely large interface between the host and its environment, and this is especially problematic for HIV-1 infected individuals. We propose to comprehensively define the chemotactic environment in the lung during health and infection. To this end, we will develop a virtual model of the immunological events ocurring in the lungs during HIV-1 infection in humans. This will allow for integration of the plethora of information on chemokine and cytokine modulation, cellular influx, and other relevant immunological factors. We will build the model based on data reported from human studies together with those we generate in a SIV/cynomolgous macaque nonhuman primate (NHP) model for HIV-1 infection and disease progression. Using methods to define cellular populations and protein and gene expression patterns within the lungs of SIV infected macaques, we will determine both local and systemic immunological mediators that are most important during nonpathologic and pathologic states, and the timing and modulation of their expression levels. This will in turn inform the model providing important mechanistic and kinetic data. Utilizing these two experimental systems will elucidate the dynamics of the immune responses within the lung, whether directed against the virus or other pathogens. The local dynamics include the complex networks of cells, cytokines, chemokines, virus, and other pathogens within interstitium and bronchoalveolar lavage fluid (BALF). Our specific aims are to use data from models of both nonhuman primate and virtual human models to: (1)Determine the homeostatic and modulated chemokine expression patterns during SIV infection in the lung, draining lymph node and blood. (2) Predict chemokine and cellular dynamics during homeostasis and HIV-1 infection in the lung, draining lymph nodes, lymph tissue and blood. (3) Identify associations between altered chemokine patterns and local cytokine production, cellular populations, virus, and opportunistic infections on the chemotactic environment in the lung during SIV/HIV-1 infection. Through this work, we will also explore the respective compositions of BAL fluid and lung interstitium and determine which is more predictive of a favorable disease outcome. Utilizing this unique approach of pairing computer and NHP models, the interaction of multiple factors that control the chemokine environment will be defined. Key parameters governing these interactions will be identified. The ability to synthesize the data generated by the experiments in the modelsallows for an understanding of the dynamics within lung in both NHP and humans during SIV/HIV-1 infection as more than the sum of its parts and will provide information useful in the generation of additional therapeutic intervention strategies. (End of Abstract)

描述(由申请人提供)： 肺部是宿主和环境之间的一个非常大的界面，这对感染HIV-1的人来说尤其有问题。我们建议全面定义健康和感染期间肺内的趋化环境。为此，我们将开发一个在人类感染HIV-1期间肺部发生的免疫事件的虚拟模型。这将允许整合过多的关于趋化因子和细胞因子调节、细胞内流和其他相关免疫因素的信息。我们将基于人类研究报告的数据以及我们在SIV/食蟹猴非人类灵长类(NHP)模型中生成的数据来构建HIV-1感染和疾病进展的模型。通过确定SIV感染猕猴肺部的细胞种群和蛋白质和基因表达模式，我们将确定在非病理和病理状态下最重要的局部和系统免疫介质，以及它们表达水平的时间和调节。这将反过来为模型提供重要的力学和动力学数据。利用这两个实验系统将阐明肺内免疫反应的动态，无论是针对病毒还是其他病原体。局部动态包括细胞、细胞因子、趋化因子、病毒和其他病原体在间质和支气管肺泡灌洗液(BALF)中的复杂网络。我们的具体目标是使用来自非人灵长类动物模型和虚拟人类模型的数据来：(1)确定SIV感染期间肺、引流淋巴结和血液中的动态平衡和调节的趋化因子的表达模式。(2)预测肺内动态平衡和HIV-1感染、引流淋巴结、淋巴组织和血液时的趋化因子和细胞动力学。(3)确定在SIV/HIV-1感染期间，趋化因子模式的改变与局部细胞因子的产生、细胞种群、病毒和肺部趋化环境中的机会性感染之间的关系。通过这项工作，我们还将探索BAL液和肺间质的各自组成，并确定哪一种更能预测有利的疾病结局。利用这种将计算机和NHP模型配对的独特方法，将定义控制趋化因子环境的多种因素的相互作用。将确定管理这些互动的关键参数。在模型中合成实验产生的数据的能力有助于理解SIV/HIV-1感染期间NHP和人类的肺内动态，而不是其各部分的总和，并将提供有助于制定额外治疗干预策略的信息。(摘要结束)