EXPRESSION OF INFLAMMATORY CYTOKINES AND INDUCIBLE NITRIC-OXIDE SYNTHASE IN BRAINS OF SIV-INFECTED RHESUS-MONKEYS - APPLICATIONS TO HIV-INDUCED CENTRAL-NERVOUS-SYSTEM DISEASE

Background: Human immunodeficiency virus type 1 (HIV-1) infection of t he central nervous system (CNS) can lead to severe impairments in cogn ition, behavior, and motor skills. The mechanism(s) by which HIV-1 ind uces CNS disease are not well understood. Recent evidence suggests tha t expression of inducible nitric oxide synthase (iNOS) and nitric oxid e (NO) may contribute to HIV-1-induced neurologic disease. We sought t o determine if these factors were present in the CNS of rhesus monkeys with simian immunodeficiency virus (SIV)-induced CNS disease. Materia ls and Methods: Total NO production in cerebral spinal fluid (CSF) fro m infected monkeys was determined by measuring nitrite (NO2-) and nitr ate (NO3-) (stable NO degradation products) utilizing Greiss reagents. in situ hybridization revealed iNOS, interferon-gamma(IFN gamma), and interleukin 1 beta (IL-1 beta) mRNA in the brains of SN-infected monk eys. Microglia were isolated from animals infected with SIV. Following stimulation with LPS, induction of iNOS mRNA in isolated microglia wa s analyzed by reverse transcriptase-polymerase chain reaction. Results : Serial CSF samples from an SIV-infected monkey reveal increased leve ls of NO2-/NO3-. In situ hybridization demonstrated iNOS, IFN gamma, a nd IL-1 beta mRNAs in post-mortem brain tissue of SN-infected monkeys. Furthermore, stimulated microglia from an SIV-infected monkey could p roduce iNOS mRNA. Conclusions: The presence of iNOS in the brain and N O2-/NO3- in the CSF indicates that NO is produced in the CN of SIV-inf ected monkeys. The data suggest that iNOS and NO may be contributing t o SIV-induced CNS disease.