DESCRIPTION (Applicant's Abstract): Despite recent advances in antiretroviral therapies, the effect of human immunodeficiency virus type one (HIV-1) on the central nervous system remains a significant cause of morbidity in affected humans. The pathogenesis of the cognitive dysfunction associated with brain disease likely revolves around productive HIV infection of brain macrophages/microglia leading to the secretion of an inflammatory cascade for neurodegreneration. The hypothesis proposed in this application is that virus-infected immunologically competent brain macrophages and microglia play central but distinctive roles in HIV-1 neuropathogenesis. This mentored clinical scientist application is designed for 5 years of support for career development from a physician to a fully competent independent scientist in academic medicine. The goal of the program is to learn the necessary technical and didactic skills to perform hypothesis-driven research. Knowledge in molecular genetics, biochemistry, immunology, neurobiology, and medical ethics through specific laboratory rotations and coursework will be initiated at both the University of Nebraska Medical Center and at Creighton University. Research activities will take place within an integrated program at the Center for Neurovirology and Neurodegenerative Disorders. Mentored research will evolve from closely supervised works into fully independent research activities. The analysis of the molecular mechanisms of HIV-1 encephalitis will involve developmental laboratory and animal model systems, drug testing and combined research activities in neuroimmunology, virology, molecular genetics and pathology. This, taken together with coursework, broad university, clinical and center support aims to permit a research experience of the highest order for grasping the principals necessary for sustained success in academic biomedical research.