Berman N E, Marcario J K, Yong C, Raghavan R, Raymond L A, Joag S V, Narayan O, Cheney P D
Department of Anatomy and Cell Biology, Marion Merrell Dow Laboratories, Kansas City, KS 66160-7400, USA.
Neurobiol Dis. 1999 Dec;6(6):486-98. doi: 10.1006/nbdi.1999.0261.
HIV-1 causes cognitive and motor deficits and HIV encephalitis (HIVE) in a significant proportion of AIDS patients. Neurological impairment and HIVE are thought to result from release of cytokines and other harmful substances from infected, activated microglia. In this study, the quantitative relationship between microglial activation and neurological impairment was examined in the simian immunodeficiency model of HIVE. Macaque monkeys were infected with a passaged, neurovirulent strain of simian immunodeficiency virus, SIV(mac)239(R71/17E). In concurrent studies, functional impairment was assessed by motor and auditory brainstem evoked potentials and by measurements of cognitive and motor behavioral deficits. Brain tissue was examined by immunohistochemistry using two markers of microglia activation, MHC-II and matrix metalloproteinase-9 (MMP-9). The inoculated animals formed two groups: rapid progressors, which survived 6-14 weeks postinoculation, and slow progressors, which survived 87-109 weeks. In the rapid progressors, two patterns of MHC-II expression were present: (1) a widely disseminated pattern of MHC-II expressing microglia and microglial nodules in cortical gray matter and subcortical white matter, and (2) a more focal pattern in which MHC-II expressing microglia were concentrated into white matter. Animals exhibiting both patterns of microglial activation showed mild to severe changes in cognitive and motor behavior and evoked potentials. All rapid progressors showed expression of MMP-9 in microglia located in subcortical white matter. In the slow progressors MHC-II and MMP-9 staining was similar to uninoculated control macaques, and there was little or no evidence of HIVE. These animals showed behavioral deficits at the end of the disease course, but little changes in evoked potentials. Thus, increases in MHC-II and MMP-9 expression are associated with development of cognitive and motor deficits, alterations in evoked potentials, and rapid disease progression.
在相当一部分艾滋病患者中，HIV-1会导致认知和运动功能障碍以及HIV脑炎（HIVE）。神经功能损害和HIVE被认为是由受感染、活化的小胶质细胞释放细胞因子和其他有害物质所致。在本研究中，在HIVE的猿猴免疫缺陷模型中检测了小胶质细胞活化与神经功能损害之间的定量关系。猕猴感染了传代的、具有神经毒性的猿猴免疫缺陷病毒毒株SIV（mac）239（R71/17E）。在同期研究中，通过运动和听觉脑干诱发电位以及认知和运动行为缺陷测量来评估功能损害。使用小胶质细胞活化的两种标志物MHC-II和基质金属蛋白酶-9（MMP-9）通过免疫组织化学检查脑组织。接种动物形成两组：快速进展者，接种后存活6-14周；缓慢进展者，存活87-109周。在快速进展者中，存在两种MHC-II表达模式：（1）MHC-II表达的小胶质细胞和小胶质结节在皮质灰质和皮质下白质中广泛分布的模式，以及（2）MHC-II表达的小胶质细胞集中在白质中的更局灶性模式。表现出两种小胶质细胞活化模式的动物在认知和运动行为以及诱发电位方面出现轻度至重度变化。所有快速进展者在皮质下白质中的小胶质细胞中均显示MMP-9表达。在缓慢进展者中，MHC-II和MMP-9染色与未接种的对照猕猴相似，几乎没有或没有HIVE的证据。这些动物在病程结束时表现出行为缺陷，但诱发电位变化很小。因此，MHC-II和MMP-9表达的增加与认知和运动功能缺陷的发展、诱发电位的改变以及疾病的快速进展相关。
