Microglial activation and neurological symptoms in the SIV model of neuroAIDS: Association of MHC-II and MMP-9 expression with behavioral deficits and evoked potential changes

HIV-1 causes cognitive and motor deficits and HIV encephalitis (HIVE) in a significant proportion of AIDS patients. Neurological impairment and HIVE a re thought to result from release of cytokines and other harmful substances from infected, activated microglia. In this study, the quantitative relati onship between microglial activation and neurological impairment was examin ed in the simian immunodeficiency model of HIVE. Macaque monkeys were infec ted with a passaged, neurovirulent strain of simian immunodeficiency virus, SIV(mac)239(R71/17E). In concurrent studies, functional impairment was ass essed by motor and auditory brainstem evoked potentials and by measurements of cognitive and motor behavioral deficits. Brain tissue was examined by i mmunohistochemistry using two markers of microglia activation, MHC-II and m atrix metalloproteinase-9 (MMP-9). The inoculated animals formed two groups : rapid progressors, which survived 6-14 weeks postinoculation, and slow pr ogressors, which survived 87-109 weeks. In the rapid progressors, two patte rns 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 exhibiti ng both patterns of microglial activation showed mild to severe changes in cognitive and motor behavior and evoked potentials. All rapid progressors s howed expression of MMP-9 in microglia located in subcortical white matter. In the slow progressors MHC-II and MMP-9 staining was similar to uninocula ted control macaques, and there was little or no evidence of HIVE. These an imals showed behavioral deficits at the end of the disease course, but litt le changes in evoked potentials. Thus, increases in MHC-II and MMP-9 expres sion are associated with development of cognitive and motor deficits, alter ations in evoked potentials, and rapid disease progression. (C) 1999 Academ ic Press.