Monocyte/Macrophages in neuroAIDS

DESCRIPTION (provided by applicant): Infection with HIV-1, the causative agent of AIDS, results in central nervous system (CNS) as well as immunological dysfunction. NeuroAIDS, the constellation of symptomatology found in individuals with cognitive and/or motor disorders, can be a devastating consequence of infection. Although it is generally accepted that the products of infected and/or activated cells of the monocytic lineage (monocytes, macrophages, and microglia) lead to CNS dysfunction in neuroAIDS, our understanding of the nature of the alterations resulting in macrophage accumulation in the brain and the nature of their injurious effects on neurons are still limited. The studies proposed here will combine in vivo studies, using the SIV/rhesus monkey model of AIDS and mouse models, to examine key pathogenic factors leading to brain macrophage accumulation, and the injurious neuronal response. In vitro studies on monocytes, macrophages, and neurons will complement these experiments to further test the molecular mechanisms involved in these effects. Three Specific Aims are proposed, in which we hypothesize that bone marrow changes, potentially due to TGFbeta, results in the production of monocytes with properties leading to increased ability to enter and accumulate in the brain. Osteopontin, discovered to be upregulated in brains in SIVE and HIVE, is postulated to play a key role in this accumulation. Macrophage accumulation and microglia activation in the brain leads neurons to respond to this altered environment, and we have identified cyclin D3 as a potential pathogenic initiator of an eventually damaging neuronal response. The effects of this expression in neurons will be investigated. These combined studies will expand our knowledge of the pathogenesis of this disorder, and should identify crucial pathways in which therapeutic or preventative interventions can be directed.