Microglia and SIV Neuropathogenesis

描述（由申请人提供）：本次更新申请的重点是神经艾滋病患者中枢神经系统（CNS）中单核细胞/巨噬细胞的运输和积累。在之前的资助期内，我们建立了血管周围巨噬细胞和实质小胶质细胞之间的免疫表型差异，并确定血管周围巨噬细胞是病毒血症和艾滋病晚期SIV感染的主要靶点。在接下来的一段时间里，我们的重点是在骨髓和血液中识别中枢神经系统血管周围巨噬细胞的潜在前体，并研究它们的激活、扩增和SIV感染。我们假设可以在骨髓和血液中发现携带病毒到中枢神经系统的单核巨噬细胞；免疫系统控制这些细胞的感染、激活和扩张；这些被感染的单核细胞的运输和积累成为血管周围巨噬细胞，导致了多产的中枢神经系统感染。我们提出三个具体目标来研究这些假设。

DESCRIPTION (provided by applicant): The focus of this renewal application is on the traffic and accumulation of monocyte/macrophages in the central nervous system (CNS) in neuro-AIDS. In the previous funding period, we established immune-phenotypic differences between perivascular macrophages and parenchymal microglia, and identified perivascular macrophages as a primary target of productive SIV infection at viremia and terminally with AIDS. Our focus in upcoming period is to identify potential precursors to CNS perivascular macrophages within the bone marrow and blood and to study their activation, expansion, and infection by SIV. We hypothesize that monocytelmacrophages, which can carry virus to the CNS, can be identified in the bone marrow and blood; the immune system controls the infection, activation, and expansion of these cells; and that traffic and accumulation of these infected monocytes that become perivascular macrophages contribute to productive CNS infection. We propose 3 specific aims to study these hypotheses. Studies in Aim 1 propose to identify monocyte/macrophages in the bone marrow and blood that have a similar immune phenotype of CNS perivascular macrophages, to define subpopulations that are SIV-infected at viremia and with AIDS, to determine the timing of latent and productive infection, and to identify populations that have similar env sequences. Studies in aim 2 propose to determine the role of the peripheral immune system and CD4 + and CD8 +specific T lymphocyte responses and CTL function in controlling infection, activation, and expansion of bone marrow and blood monocyte/macrophages with immune phenotypes similar to CNS perivascular macrophages. Studies in aim 3 propose to define the timing of SIV-infected monocyte entry that contributes to productive infection of the CNS.