Chemokine Dynamics in the HIV-1/SIV Infected Lung

HIV-1/SIV 感染肺中的趋化因子动态

基本信息

批准号：
6930981
负责人：
Denise E Kirschner
金额：
$ 51.51万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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

项目摘要

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）：肺是宿主与其环境之间极大的界面，这对于HIV-1感染的个体尤其有问题。我们建议在健康和感染期间全面定义肺中的趋化环境。为此，我们将在人类的HIV-1感染期间开发出一种免疫事件的虚拟模型。这将允许整合有关趋化因子和细胞因子调节，细胞流入以及其他相关免疫学因素的大量信息。我们将根据人类研究报告的数据以及我们在SIV/cynomolgous猕猴非人类灵长类动物（NHP）模型中生成的模型建立该模型，用于HIV-1感染和疾病进展。使用方法来定义SIV感染猕猴肺中的细胞种群，蛋白质和基因表达模式，我们将确定在非人性和病理状态下最重要的局部和全身免疫学介质，以及其表达水平的时间和调节。这反过来将为提供重要的机械和动力学数据的模型提供信息。使用这两个实验系统将阐明肺部免疫反应的动力学，无论是针对病毒还是其他病原体。局部动力学包括细胞，细胞因子，趋化因子，病毒和其他病原体的复杂网络，以及支气管肺泡灌洗液（BALF）。我们的具体目的是使用非人类灵长类动物和虚拟人类模型模型的数据来：（1）确定肺部SIV感染期间的稳态和调制趋化因子表达模式，排干淋巴结和血液。（2）预测肺部稳态和HIV-1感染期间的趋化因子和细胞动力学，排出淋巴结，淋巴组织和血液。（3）确定趋化因子模式与局部细胞因子的产生，细胞种群，病毒和机会性感染之间在SIV/HIV-1感染期间肺趋化环境上的关联。通过这项工作，我们还将探索BAL液和肺间质的各自组成，并确定哪些更可预测有利疾病的结果。利用配对计算机和NHP模型的独特方法，将定义控制趋化因子环境的多种因素的相互作用。将确定控制这些交互的关键参数。模型手套中实验生成的数据的能力，以了解SIV/HIV-1感染期间NHP和人类中肺部的动态的能力，而不是其部分的总和，并将提供有用的信息，可用于生成其他治疗干预策略。（抽象的结尾）