HIV encephalopathy (HIVE) is recognized as a major complication of HIV infection, yet there are many unknown regarding the role of direct viral infection in its pathogenesis, including which cells harbor virus and whether some virus strains are more likely to invade the nervous system. The central hypothesis of this proposal is that virus tropism for cells of the central nervous system is a critical determinant in the development of HIVE, and that understanding this relationship will lead to the development of a rational approach for its treatment. We will approach this problem with an in vitro system consisting of cultured microglia, oligodendrocyte and astrocytes obtained from adults brain, in conjunction with a cell line. NTera 2, that can be differentiated into post-mitotic neurons. Three specific aims are proposed: in the first aim we will address the hypothesis that HIV microglial-tropism and macrophage-tropism may be separable, and survey both existing and newly isolated viruses to compare replication in microglia and macrophage. We will also adapt HIV strains of growth in microglia and, using linker-substitution mutants, analyze the role of the HIV-1 LTR in microglial replication. The findings from this portion of the proposal may help explain the finding that HIVE develops in only a subset of infected individuals, in spite of the fact that most harbor macrophage-tropic strains. In the second aim we will address the questions of whether oligodendrocyte are injectable by HIV strain served from the central nervous system or peripherally, and explore the possibility that infected microglia could injure oligodendrocyte. This aim will address the mechanisms underlying myelin pallor, the most frequent pathological correlate of HIVE. In the third aim, we will explore the infectability of undifferentiated and differentiated NTera 2 cells by either cell-free or cell-associated mechanisms, and will examine the neurotoxicity of infected microglia using the specialized functions characteristic of these post mitotic neurons. This aim will address the critical role of neurons in the development of dementia using human cells exclusively. The results obtained will help us understand the pathogenesis and pathophysiology of HIVE, and the role of HIV in its development. They will be important in the future design of treatment protocols.