Chemokine Dynamics in the HIV-1/SIV Infected Lung

描述（由申请人提供）： 肺是宿主与其环境之间的一个非常大的界面，这对于HIV-1感染者来说尤其成问题。我们建议全面定义肺在健康和感染期间的趋化环境。为此，我们将开发一个虚拟模型的免疫事件发生在肺部在人类感染HIV-1。这将允许整合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子的过多信息。我们将根据人类研究报告的数据以及我们在HIV-1感染和疾病进展的SIV/食蟹猴非人灵长类动物（NHP）模型中生成的数据构建模型。使用的方法来定义细胞群体和蛋白质和基因表达模式内的SIV感染的猕猴的肺，我们将确定在非病理和病理状态，其表达水平的时间和调制是最重要的局部和全身免疫介质。这将反过来为模型提供重要的机械和动力学数据。利用这两个实验系统将阐明肺内免疫反应的动力学，无论是针对病毒还是其他病原体。局部动力学包括肺泡和支气管肺泡灌洗液（BALF）中细胞、细胞因子、趋化因子、病毒和其他病原体的复杂网络。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稳态和调节的趋化因子表达模式。(2)在肺、引流淋巴结、淋巴组织和血液中的稳态和HIV-1感染期间预测趋化因子和细胞动力学。(3)确定SIV/HIV-1感染期间肺部趋化环境中改变的趋化因子模式与局部细胞因子产生、细胞群体、病毒和机会性感染之间的关联。通过这项工作，我们还将探索BAL液和肺结核各自的成分，并确定哪种成分更能预测有利的疾病结局。利用这种独特的配对计算机和NHP模型的方法，控制趋化因子环境的多个因素的相互作用将被定义。将确定支配这些相互作用的关键参数。综合模型中实验产生的数据的能力有助于理解SIV/HIV-1感染期间NHP和人类肺内的动力学，而不仅仅是其部分的总和，并将为产生额外的治疗干预策略提供有用的信息。 (End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)