Microglia and SIV Neuropathogenesis

描述(申请人提供)：此续期申请的重点是神经艾滋病患者中枢神经系统(CNS)中单核/巨噬细胞的交通和积聚。在之前的资助期间，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。我们在未来一段时期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细胞，并研究它们的激活、扩张和SIV感染。我们假设，可以在骨髓和血液中识别出能够将病毒携带到CNS的单核巨噬细胞；免疫系统控制着这些细胞的感染、激活和扩张；这些被感染的单核细胞成为血管周围巨噬细胞，运输和积累有助于产生CNS感染。我们提出三个具体目标来研究这些假说。 目标1中的研究建议鉴定骨髓和血液中具有类似中枢神经系统血管周围巨噬细胞免疫表型的单核/巨噬细胞，确定病毒血症和艾滋病时SIV感染的亚群，确定潜伏感染和生产性感染的时间，以及识别具有相似env序列的人群。目标2中的研究建议确定外周免疫系统、CD4和CD8特异性T淋巴细胞反应和CTL功能在控制免疫表型类似于中枢神经系统血管周围巨噬细胞的骨髓和血液单核/巨噬细胞的感染、激活和扩张中的作用。目标3中的研究建议确定SIV感染的单核细胞进入导致中枢神经系统生产性感染的时间。

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.