In addition to the severe immunodeficiency resulting from infection with the human immunodeficiency virus type-1 (HIV-1), a significant proportion of individuals develop neurologic dysfunctions referred to collectively as the HIV-1-associated motor/cognitive disorder (HMCD). Simian immunodeficiency virus (SIV) infection of rhesus macaques serves as an excellent model system for HIV-1 entry into and replication within the central nervous system (CNS). How infection of the CNS by HIV-1 or SIV leads to neurologic impairment is not fully understood. The overall objective of this proposal is to identify virus/host interactions within the CNS of SIV infected rhesus macaques that contribute to motor/cognitive deficits. Our hypothesis is that there are brain-specific cellular genes that are differentially expressed during SIV encephalitis (SIVE) and there are brain- specific cellular proteins whose activities are modulated by interaction with the SIV Nef protein. Furthermore, we propose that these changes in gene expression and protein function contribute to the neurologic impairments associated with infection by SIV. In order to address these issues, gene expression profiles of brain tissues from macaques without SIVE or in the early stages of SIVE, will be generated using the recently developed serial analysis of gene expression (SAGE) technology. This approach will determine the relative levels of expression of individual mRNAs present in macaque brains and will identify genes that are differentially expressed in brain cells during early SIVE relative to non-encephalitic brain tissues. The numbers, locations, and types of brain cells actively transcribing differentially expressed mRNAs will be determined by in situ hybridization/immunohistochemistry, and their relationship to SIV productively infected cells with be examined. In parallel, macaque brain proteins that interact with SIV Nef will be identified by screening a brain cDNA expression library for Nef binding partners using established yeast 2-hybrid methods. Modulation of intracellular locale or enzymatic activity of interacting proteins by Nef will be comprehensively characterized. These data will provide mechanistic insight into how SIV alters the genetic and biochemical environment within the brain, thereby identifying genes and gene products that might be altered by HIV-1 replication in humans and which might serve as eventual targets for therapeutic interventions.
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