Monocytes in HIV Encephalitis

描述(由申请者提供)：HIV感染者有广泛的 神经疾病的范围从轻微的认知和运动障碍 (Mcmd)至坦率痴呆(HIV相关痴呆综合征，HIVD)。而当 MCMD的病理基础不明，HIV脑炎(HIVE)是一种已知的 HIVD的病理基础。中枢神经系统的大量激活和感染 巨噬细胞是蜂房的特征，令人惊讶的是，几乎没有证据表明直接 神经胶质细胞感染。激活和感染中枢神经系统的相对作用 巨噬细胞在调节神经损伤中的作用尚不清楚。我们假设 HIV相关的mcmd与体内巨噬细胞的病理性激活有关 中枢神经系统。此外，这种激活还提供了丰富的宿主靶细胞 艾滋病毒的感染和复制以及随后的蜂窝和HIVD的发展。 不幸的是，目前还没有记录激活的巨噬细胞的方法 在中枢神经系统内。我们建议扩展我们在猿猴艾滋病模型中的发现， 对感染艾滋病毒的人进行测试，并验证以下假设：放射性配基 3D-PET中的11C-PK11195将检测到激活的巨噬细胞的存在 HIV感染者的中枢神经系统。通过比较神经认知发现，以及 HIV感染的外周和中枢标志物以及我们希望的PK11195 PET 建立中枢神经系统巨噬细胞活化的临床检测方法。在特定目标中1WE 将对艾滋病毒感染对象进行横断面研究，并适当 控制以确定放射性配基的结合之间的关系 11C-PK11195在3DPET成像和神经系统疾病中的应用所有的科目都将是 接受一系列神经认知测试：接受MRI和PK11195-PET成像 以及艾滋病毒滴度和CD4计数的血清检测。我们假设那些 患有MCMD或HIVD的受试者将有更高的PK11195结合和保留 与中枢神经系统巨噬细胞活化增强一致。在特定目标2WE中 是否会纵向跟踪有发展风险的艾滋病毒感染者 痴呆症。每隔6个月，受试者将接受一系列 神经认知检查，血清和脑脊液分析，头部MRI和C-11PK11195 PET。我们 假设在发生神经疾病之前与 活化的中枢神经系统巨噬细胞，PET扫描将显示结合增加和 保留PK11195。如果神经系统疾病症状学进展，这是 将伴随着3DPET上PKLL95的持续上升，成功 治疗干预将与PET信号降低相关。这个 这些实验的结果将有助于确定诊断的临床测试 慢病毒脑炎和帮助识别有感染风险的人群 发展成神经性疾病。他们还将允许开发标记 目的：评估未来治疗对阻止肿瘤的发展和进展的疗效。 MCMD和HIVD。

DESCRIPTION (provided by applicant): HIV infected individuals develop a wide spectrum of neurologic disease ranging from minor cognitive and motor deficits (MCMD) to frank dementia (HIV-associated dementia complex, HIVD). While the pathologic substrate of MCMD is unknown, HIV encephalitis (HIVE) is a known pathologic substrate of HIVD. Abundant activation and infection of CNS macrophages characterize HIVE, with surprisingly little evidence of direct neuroglial infection. The relative role of activated and infected CNS macrophages in mediating neurologic damage is not known. We hypothesize that HIV associated MCMD is related to pathologic activation of macrophages within the CNS. Further this activation provides abundant host target-cells for infection and replication of HIV and subsequent development of HIVE and HIVD. Unfortunately there are no current means of documenting activated macrophages within the CNS. We propose to extend our findings from the simian AIDS model, to humans infected with HIV and test the hypothesis that: the radioligand 11C-PK11195 in 3D-PET will detect the presence of activated macrophages in the CNS of HIV infected subjects. By comparing neurocognitive findings, and peripheral and central markers of HIV infection and PK11195 PET we hope to establish a clinical measure of CNS macrophage activation. In Specific Aim 1we will perform a cross sectional study of HIV infected subjects and appropriate controls to determine the relationship between binding of the radioligand 11C-PK11195 in 3D PET imaging and neurologic disease. All subjects will be given a battery of neurocognitive testing: undergo MRI and PK11195-PET imaging and serum testing for HIV titers and CD4 count. We hypothesize that those subjects with MCMD or HIVD will have elevated binding and retention of PK11195 consistent with increased activation of CNS macrophages. In Specific Aim 2we will longitudinally follow HIV infected subjects at risk for developing dementia. At 6-month intervals, subjects will undergo a battery of neurocognitive exams, serum and CSF analysis, head MRI and C-11PK11195 PET. We hypothesize that prior to developing neurologic disease associated with activated CNS macrophages, PET scans will demonstrate elevated binding and retention of PK11195. If neurologic disease symptomatology progresses, this will be accompanied by persistent elevation of PKlll95 on 3D PET, Successful therapeutic intervention would be associated with decreased PET signal. The results of these experiments will help define clinical tests for diagnosing lentiviral encephalitis and help identify infected populations at risk of developing neurologic disease. They will also permit the development of markers to assess efficacy of future therapy to arrest development and progression - of MCMD and HIVD.