The goal of this proposal is to understand the unique role of the central nervous system (CNS) microglia in regulating immune responsiveness. Microglia are the major resident antigen presenting cells and source of infectious HIV within the CNS. In vitro and in vivo approaches will be used to understand the contribution of the microglia in the pathobiology of HIV infection, especially as it relates to the persistence of virus in the presence of a nominally vigorous antiviral immune response. A novel protocol will be used to isolate heterogeneous clonal microglia cells from adult mouse brain progenitors for in vitro analysis. Surface phenotype of the clones will be correlated with the ability to process and present antigen to both CD4+ and CD8+ T cells specific for HIV epitopes. Phenotype, cytokine patterns and costimulatory molecules expressed by microglia clones which induce anergy or programmed cell death will be compared to microglia clones which activate T cells. For in vivo analysis, transgenic (TG) mice which express HIV antigens in either parenchymal microglia or perivascular microglia under control of the c-fms promoter will be made. TG mice expressing HIV antigens under control of this promoter will express antigen in all differentiated cells of the monocyte lineage, including microglia. Bone marrow chimeras using non TG donor cells transplanted into TG mice will limit antigen expression to parenchymal microglia. The reverse protocol, TG bone marrow to non TG recipients, which will localize antigen expression to peripheral microglia. Control TG mice will express the HIV antigens in astrocytes under control of the GFAP promoter Transfer of HIV antigen- specific CD4+ and CD8+ T cells will determine effects of microglia antigen expression on disease induction and pathology. In addition, we will exploit the cross reactivity between an HIV CD8 epitope (expressed by the transgene) and the CD8 epitope of mouse hepatitis virus. These experiments will determine if an upper respiratory infection by a heterologous virus, including CTL which cross react with an HIV antigen expressed in microglia or astrocytes, can induce CNS pathology. Finally, we will examine the induction of tolerance to the HIV antigens expressed within the microglia and astrocytes in the TG mice as a model for the progression of AIDS in the presence of vigorous effector T cell populations.