Unique impact of SIV on monocyte CNS trafficking

描述（由申请人提供）：单核细胞在人类免疫缺陷病毒（HlV）相关痴呆的发病机制中起核心作用。它们被认为促进了病毒的神经入侵，充当了病毒进入大脑的“特洛伊木马”。然而，关于HIV感染中单核细胞脑募集的许多方面仍未明确。我们假设一个独特的单核细胞脑迁移程序在HIV感染（相对于其他病原体感染）时被触发。特异性目的1将定义猴免疫缺陷病毒（SIV）感染触发的体外单核细胞迁移谱（与巨细胞病毒、沙门氏菌和李斯特菌感染相比），以响应中枢神经系统特异性趋化因子信号，这些信号与观察到的荧光素+单核细胞脑浸润增加有关。在特定目标2中，我将检查siv感染单核细胞的趋化因子反应，以确定参与促进单核细胞持续CMS募集的自分泌调节机制。我的研究结果有望为非人类灵长类艾滋病模型中单核细胞神经浸润的机制提供新的见解，并可能导致新的药物靶向或治疗策略，以抑制异常的单核细胞神经浸润（通过靶向特定的单核细胞亚群或它们的运输信号）。

DESCRIPTION (provided by applicant): Monocytes play a central role in the pathogenesis of human immunodeficiency virus (HlV)-associated dementia. They are thought to facilitate viral neuroinvasion, serving as "Trojan horse" for virus entry into the brain. However, many aspects regarding monocyte brain recruitment in HIV infection remain undefined. We hypothesize that a unique monocyte brain migratory program is triggered upon HIV infection (versus infection with other pathogens). Specific aim 1 will define in vitro monocyte migratory profiles triggered upon simian immunodeficiency virus (SIV) infection (compared to infection with CMV, Salmonella and Listeria) in response to CNS-specific chemokine signals which correlate with observed increased fluorescein+ monocyte brain infiltration in vivo. In specific aim 2, I will examine chemokine responses of SIV-infected monocytes to identify autocrine regulatory mechanisms involved in promoting continued monocyte CMS recruitment. My findings are expected to provide novel insights into mechanism(s) of monocyte neuroinvasion in the nonhuman primate model for AIDS and may lead to novel drug targeting or treatment strategies that inhibit aberrant monocyte neuroinfiltration (by targeting specific monocyte subsets or their trafficking signals).