Microglia are a relatively under-recognized, widely distributed cell population within brain parenchyma constituting about 1-2 percent of all cells. They are considered to be of bone marrow origin and are derived from the monocyte/macrophage lineage. Resident microglia in the brain parenchyma function as important immunoregulatory cells which can both contribute to T cell activation responses in the brain, and also protect the CNS by inhibiting T cell function. Similar to monocytes and macrophages, microglia are susceptible to infection by numerous viruses that infect the CNS, including HIV-1. Indeed, microglia represent the major HIV-infected cell in the CNS and increasing evidence supports early infection of parenchymal microglia even in asymptomatic patients. The role of microgIia as antigen-presenting cells (APC) is controversial. MHC class II expression can be upregulated on microglia in response to neuronal damage, infection, or inflammation and data obtained from some in vitro studies suggest they are able to stimulate CD4+ T cells under certain circumstances. However, other studies suggest that microglia function as relatively inefficient ARC compared to professional APC found in the periphery such as dendritic cells. Studies into the specific role of microglia as APC in vivo models is lacking, as are studies to investigate the interaction of microglia with CD8+ CTL. HIV-1 infected cells shed the envelope glycoprotein gp120, that may diffuse and interact with a variety of CNS cells. Infected microglia express gp120, and there is growing evidence that microglia may injure neurons through release of gp120. Transgenic mice constitutively overexpressing gp120 in the brain display a spectrum of neuronal and glial changes resembling abnormalities in brains of HIV-infected humans. We have developed a mouse model in which the migration, accumulation and activity of gp120-specific T cells can be investigated following adoptive transfer into recipient animals expressing gp120 in the CNS. In addition, we propose to extend this model to include evaluation of endogenous T cell responses to CNS/gp120 so that qualitative and quantitative differences in antigen-presentation between microglia and peripheral APC can be determined. Such tools will allow us to carefully dissect the critical role played by microglia in modulating HlVgp120-specificT cell responses in the CNS.
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