This revised Program Project application is a competitive renewal focused on understanding impairment of lung host defense in the context of human immunodeficiency virus (HIV) infection. Pulmonary dysfunction is a major outcome of impaired immunity due to HIV and results in significant clinical morbidity and frequent mortality from opportunistic pathogens. Considerable progress was made in establishing biological systems to better define the pathogenesis of impaired pulmonary defense during the initial years of the Program. New insights into the interaction of HIV with alveolar macrophages as well as lung cell interactions with Pneumocystis carinii and Mycobacterium avium were derived from the component projects. While a cohesive and dynamic set of collaborations established in the initial Program forms the basis for this renewal application, new projects and cores have been developed to incorporate technology and systems important in fulfilling the scientific aims. In this proposed renewal, considerable emphasis is placed on translating insights from laboratory studies into novel therapeutic strategies aimed at reconstituting lung defense against specific pathogens, in part by exploiting small animal models and exploring methods of pulmonary delivery of cytokines and soluble receptors. The Program renewal features four projects and four supporting cores. The component projects are: A. Ezekowitz: The Macrophage Mannose Receptor in Pneumocystis carinii Infection; J. Brain: Lung Delivery of Therapeutic Agents: Fate and Efficacy; H. Kornfeld, H. Remold, and R. Young: Defense Mechanisms of Lung Cells Against Mycobacterium Tuberculosis; J. Groopman and E. Terwilliger: Effects of HIV and CMV upon the Alveolar Macrophage. The cores include: Administrative (J. Groopman); Cell Services (H. Koziel); Ultrastructural Analysis (A. Warner); Animal Models (A. Harmsen). The continuation of successful projects from the initial Program, the decision to shift from unsuccessful prior aims and to initiate new projects, the targeting of emerging technologies such as gene therapy, the incorporation of small animal models of opportunistic infection, and the desire to address pressing public health issues such as tuberculosis, provide the foundations for structuring the proposed Program.
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