? ? 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) ? ?
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