Pulmonary infections are frequent complications of HIV infection and a common cause of death in patients with AIDS. Pulmonary pathogens complicating HIV infection include bacteria (pneumonia), fungi (Pneumocystis carinii), and mycobacteria (tuberculosis). Antimicrobial therapy is possible for many of these infections, but such therapies may not be available in developing countries and antibiotic resistance is an increasing problem. A more direct solution to the problem of HIV-related pulmonary infections is to correct the defects in host defense caused by HIV infection. The long-term objective of this Project is to identify new methods to augment host defense against pulmonary infection in HIV-infected patients. In this application, we will direct and coordinate a group of established investigators in host defense to conduct research targeted to HIV-related pulmonary infections. The Project theme is to explore genetic approaches to enhance the delivery of immune effector cells into lung tissue in order to augment clearance of HIV-related pulmonary infections. We postulate that genetic approaches can be used to either increase local signals for recruitment of immune effector cells into infected lung tissue or to increase the pool of circulating effector cells available for recruitment. Four interactive research projects will address: 1. CXCR3 ligands as signals for lymphocyte recruitment in host defense against P. carinii (Dr. Shellito) 2. CD4-independent vaccine strategies for pulmonary infections (Dr. Kolls) 3. Prime/boost vaccination strategies for pulmonary tuberculosis (Drs. Ramsay, Mason) 4. Strategies to increase hematopoietic responses to bacterial pneumonia (Drs. Schwarzenberger, Nelson, and Bagby) The research projects will be supported by 3 core components: Administrative Core (Dr. Shellito), Immunology Core (Dr. Zhang), Vector Core (Dr. Reiser) Project research will develop and validate new methods of immune augmentation in animal models of pulmonary infection relevant to HIV infection. Data generated will then provide a foundation for future applications to HIV-infected patients.
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