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中中枢神经系统（CNS）中单核细胞/巨噬细胞的运输和蓄积。在前一个资助期，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作为病毒血症和艾滋病晚期SIV感染的主要靶点。在接下来的时间里，我们的重点是确定骨髓和血液中CNS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，单核细胞巨噬细胞，可以携带病毒到中枢神经系统，可以在骨髓和血液中识别;免疫系统控制这些细胞的感染，激活和扩展;和交通和积累这些感染的单核细胞，成为血管周围的巨噬细胞有助于生产性中枢神经系统感染。我们提出了3个具体的目标来研究这些假设。 目的1中的研究提出鉴定骨髓和血液中与CNS血管周围巨噬细胞具有相似免疫表型的单核细胞/巨噬细胞，以定义在病毒血症和AIDS时SIV感染的亚群，以确定潜伏性和生产性感染的时间，并鉴定具有相似env序列的群体。目的2中的研究提出确定外周免疫系统和CD 4+和CD 8+特异性T淋巴细胞应答以及CTL功能在控制免疫表型与CNS血管周围巨噬细胞相似的骨髓和血液单核细胞/巨噬细胞感染、活化和扩增中的作用。 目的3中的研究提出确定SIV感染的单核细胞进入CNS的时间，这有助于CNS的生产性感染。

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.