The mechanism by which human immunodeficiency virus type-1 (HIV-1) causes central nervous system (CNS) disease remains unknown, although regional neuronal loss is probably an important contributor to this process. Neuronal loss in AIDS is believed to occur by an indirect mechanism, presumably mediated by soluble, diffusible neurotoxins, since HIV-1 does not productively infect neurons. Candidate neurotoxins include cytokines, reactive oxygen intermediates, and HIV-1 gene products. The proposed studies will focus on the experimental infection of macaque monkeys with neurovirulent simian immunodeficiency virus (SIV), as a model system to study molecular aspects of the neuropathogenesis of AIDS.
The specific aims will address the role of NFkappaB activation in the neuropathogenesis of SIV infection, using immunocytochemistry to detect the NFkappaB subunits, p50 and p65, and to determine whether they are activated (translocated to cell nuclei) in brain tissues from macaques with symptomatic, SIV-induced, CNS disease. In vitro experiments will also be performed to assess the role of persistent NFkappaB activation in the release of neurotoxins from SIV-infected simian macrophages. These studies will be conducted by treating SIV-infected macrophages with compounds known to promote or block the activation of NFkappaB, followed by quantitation of the neurotoxin release, using primary human neurons as target cells. These studies are expected to provide important insights into the neuropathogenesis of AIDS and may perhaps lead to new therapeutic strategies for this disease.
| Hodge, S; Novembre, F J; Dewhurst, S (1998) Endogenous tumor necrosis factor-alpha contributes to lymphoproliferation induced by simian immunodeficiency virus variant, SIVsmmPBj14. Immunol Lett 63:49-51 |
