Monocytes in HIV Encephalitis

描述（由申请人提供）：艾滋病毒感染者发展广泛的 一系列神经系统疾病，从轻微的认知和运动缺陷 （MCMD）到坦率痴呆（HIV相关痴呆综合征，HIVD）。而 MCMD的病理基质是未知的，HIV脑炎（HIVE）是已知的 HIVD的病理基质。中枢神经系统的大量激活和感染 巨噬细胞是HIVE的特征，令人惊讶的是， 神经胶质细胞感染活化和感染CNS的相对作用 巨噬细胞在介导神经损伤中的作用尚不清楚。我们假设 HIV相关MCMD与体内巨噬细胞的病理性激活有关， CNS。此外，这种激活为免疫调节提供了丰富的宿主靶细胞。 HIV感染和复制以及随后发生HIVE和HIVD。 不幸的是，目前还没有记录活化巨噬细胞的方法 在CNS中。我们建议从猿类艾滋病模型中扩展我们的发现， 对感染艾滋病毒的人进行检测，并检验以下假设： 3D-PET中的11 C-PK 11195将检测到在细胞中存在活化的巨噬细胞。 HIV感染受试者的CNS。通过比较神经认知发现， 外周和中枢HIV感染标志物和PK 11195 PET，我们希望 建立CNS巨噬细胞活化临床测量。具体目标1 将对HIV感染者进行横断面研究， 确定放射性配体结合之间关系的对照 11 C-PK 11195在3D PET成像和神经系统疾病中的应用所有受试者将 给予一系列神经认知测试：接受MRI和PK 11195-PET成像 以及艾滋病毒滴度和CD 4计数的血清检测。我们假设那些 MCMD或HIVD受试者的PK 11195结合和保留增加 与中枢神经系统巨噬细胞的活化增加一致。具体目标2 we 将纵向跟踪HIV感染受试者， 痴呆每隔6个月，受试者将接受一组 神经认知检查、血清和CSF分析、头部MRI和C-11 PK 11195 PET。我们 假设在发展与以下疾病相关的神经系统疾病之前 激活的CNS巨噬细胞，PET扫描将显示结合升高， 保留PK 11195。如果神经系统疾病进展， 将伴随3D PET上PK 11195的持续升高，成功 治疗干预将与PET信号降低相关。的 这些实验的结果将有助于确定诊断的临床试验 慢病毒性脑炎，并帮助确定感染人群的风险， 发展成神经系统疾病它们还将允许开发标记 评估未来治疗的有效性，以阻止发展和进展- 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.