The broad objective of this project is to develop a SIV macaque model of pediatric AIDS that can be used to elucidate the neuropathogenesis of human immunodeficiency virus (HIV) infection. The investigator has three specific aims the first of which is to try to determine the temporal distribution and cellular targets of SIV in the central nervous system (CNS) of fetal and neonatal macaques inoculated with SIVmac at different stages of development. CNS tissue from 12 fetuses, inoculated at different stages of gestation and 10 inoculated on the same day of gestation and serially sacrificed, will be provided for study by collaborators at the California Regional Primate Research Center. The distribution of virus and identity of infected cells will be determined by immunohistochemistry and in situ hybridization. The second goal of the investigator is to attempt to develop an in vitro reaggregate brain culture system to examine mechanisms of SIV neuropathogenesis. This section has three subparts, the first of which is to try to assess the neuropathologic potential of different SIV isolates, molecular clones and recombinant viruses. The second is to evaluate the role of possible viral cofactors such as cytomegalovirus (CMV) in SIV neuropathogenesis. The third is to evaluate possible lentiviral-related toxins such as SIV-gp130, cytokines and quinolinic acid.These tasks will be accomplished by in vitro inoculation of reaggregated brain cultures with various isolates of SIV or potential toxins. The cultures will be evaluated by histopathology, immunohistochemistry for cellular and viral proteins, in situ hybridization for viral nucleic acid and biochemical analysis for potential toxins. The third specific aim is to attempt to test potential SIV-associated neurotoxins for their effect in vivo. This goal is designed to test the in vivo relevance of the findings in the second specific aim. This will be accomplished by chronic intrathecal administration of putative neurotoxins to normal uninfected infant rhesus macaques. The animals will then be monitored using the same neurodevelopmental test used in SIV-infected macaques. This will allow a comparison between the CNS effects of SIV and putative neurotoxins.
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