Microglia-passaged simian immunodeficiency virus (SIV) induces pathological and physiological abnormalities in the monkey central nervous system (CNS)

We have investigated whether infection of rhesus monkeys with a microglia-passaged strain of SIV could induce CNS damage and dysfunction. The passage of SIV through microglia resulted in an enrichment of unique quasispecies of virus, which is neuropathogenic when inoculated into macaques. Within the brains of infected animals T cells and macrophages were present. The T cells were mainly CD8+, and SIV-specific cytotoxic T lymphocytes were identified in the CSF and brains of monkeys following SIV infection. In addition to the inflammatory cells the expression of several pro-inflammatory cytokines were identified in the brain, as was expression of the inducible form of nitric oxide synthase (iNOS). Thus both cellular and soluble factors are present that can result in CNS injury. Three distinct measures of CNS function were abnormal in the SIV-infected animals. Neurophysiological analysis of both auditory and visual evoked potentials indicated that the SIV-infected monkeys demonstrated abnormal responses- Behavioral testing revealed deficits in cognitive and motor performance following infection. Finally, measurement of body temperature and activity by radiotelemetry exposed a post-infection disruption in the circadian rhythm. These results show that the microglia-passaged SIV can induce structural and functional abnormalities in the CNS. Our system provides a model to investigate the pathogenesis of AIDS dementia and to assess drugs with potential therapeutic benefits.