The majority of HIV-infected adults and children suffer neurological impairment. Studies of HIV-associated dementia complex have repeatedly demonstrated that HIV-1 replicates in cells of macrophage lineage (microglia), and virus cultured from the brains usually macrophage- tropic. Studies of the pathogenesis of HIV in the CNS have been limited by the difficulty of studying the progression of disease. The timing and mechanisms of viral entry into the brain and the viral determinants of neurotropism are incompletely understood. the SIV/macaque model provides an excellent system to determine the early events in CNS infection and to reconstruct the events leading to terminal disease. Genetically defined clones of SIV make it possible to investigate the viral genes that contribute to cell tropism and gene expression in the CNS. Our hypothesis is that a tropism for macrophages is a prerequisite for both HIV and SIV to infect cells in the CNS. However, further selection for virus replication in CNS cells is necessary for infection and progression of disease. These neurotropic viruses enter the brain through the blood- brain barrier by mechanism(s) which may involve expression of cell adhesion molecules on virus or virus-infected cells, and replicate in macrophages in brain. Pathological changes in the CNS may be a function of the level of viral replication in target cells. This interdisciplinary program on the SIV/macaque model will allow us to investigate this hypothesis both in vivo and in vitro. Project 1 will investigate the timing of viral entry into the brain, the mechanisms by which the virus crosses the blood-brain-barrier and the events in cells of the CNS that lead to disease. Project 2 will examine how cellular adhesion molecules affect viral entry, cell tropism and the host response to the virus. Project 3 will examine the genetic basis of macrophage- tropism and neurotropism. The molecular events involved in SIV infection in the brain and in primary brain cells (microglia and endothelial cells). This program approaches the development of lentivirus-induced CNS disease from three disciplines, pathobiology, cell biology and molecular biology and contribute to the overall understanding of the viral and cellular mechanisms that contribute to CNS encephalopathy in SIV and HIV. These studies will provide a basic understanding of how HIV enters the brain and causes neural dysfunction and will provide information critical to the development of rational interventional and therapeutic approaches to HIV-induced disease.