IMMUNOPHENOTYPIC DIVERSITY OF BRAIN MACROPHAGES: IMPLICATIONS FOR NEUROAIDS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infection of humans with HIV or macaques with SIV often leads to an encephalitis (HIVE or SIVE) characterized by perivascular accumulations of macrophages and multinucleated giant cells, many of which are productively infected. It is assumed that the development of SIVE/HIVE is associated with increased migration (and retention) of circulating monocytes into the brain. The immigration of these monocytes into the brain would facilitate neuroinvasion and provide additional cells for infection. Direct assessment of this hypyothesis has been frustrated by the lack of specific markers that can easily differentiate among perivascular macrophages, recently immigrated monocytes, and parenchymal microglia. Recently, expression of CD14 and CD45 in conjunction with CD11b has been used to differentiate parenchymal microglia (CD11b+ CD14¿CD45¿) from perivascular macrophages (CD11b+ CD14+CD45+) and define the latter as the primary cell type productively infected in the CNS. It was clear, however, that the population of SIV-infected cells that shared expression of CD11b, CD14 and CD45 was heterogeneous. This suggested that we might be looking at several populations of cells including those that had recently immigrated from the blood. To assess this further and try to define the immunophenotypes of additional populations of brain macrophages, including those that had recently entered the CNS, we performed multilabel confocal microscopy for a variety of cell markers combined with in situ hybridzation (ISH) for SIV. The markers used included CD11b, CD14, CD45, myeloid histocyte antigen (clone MAC387), myeloid related proteins 8 (MRP8) and 14 (MRP14), CD68, HAM56, LN5 and CD163. The presence of MAC387+, MRP8+, MRP14+ cells not infected by SIV could represent either recently recruited monocyte/macrophages or a population of macrophages resistant to infection. Lastly, CD163 appears to label ¿activated¿ microglia as no labeling of parenchymal cells was seen in normal animals, while in animals with encephalitis there labeling was extensive.