author's abstract.) Neurological involvement frequently accompanies the acquired immunodeficiency syndrome (AIDS) and has been referred to as AIDS dementia complex (ADC). The cell that appears to be the in vivo reservoir of HIV is the monocyte/macrophage. Recently, these investigators reported that HIV- infected macrophages produce a neurotoxin that is capable of altering normal brain structure and function in vitro. The overall goal of this project is to characterize further how HIV causes brain damage, to determine if the damage is confined to a neural subset, and to explore the role CMV plays in AIDS dementia. The proposed studies will employ a human brain aggregate culture system which, when exposed to a factor elaborated by HIV-infected macrophages, reproduced many of the pathologic changes observed in brains from patients with AIDS-associated dementia. Once the mechanism of brain damage is more precisely elucidated, attempts will be made to reverse the effects in a brain cell aggregate culture system.
The specific aims are: (1) to characterize biochemically the neurotoxin produced by HIV-infected macrophages; (2) to determine whether different regions of the brain show different sensitivities to the HIV-infected macrophage neurotoxin and whether one specific cellular subset is affected more than others; (3) to determinewhether CMV can potentiate neurotoxicity by inducing the production of a macrophage-derived neurotoxic factor or exacerbating the production of HIV-infected macrophage soluble factor; and (4) to use several different approaches to reverse the toxicity observed in brain aggregates treated with virus-infected macrophage soluble factor including antiviral agents alone or in combination with steroids or antagonists to excitatory neurotransmitter amino acids known to be neurotoxic.
| Pulliam, L; Gascon, R; Stubblebine, M et al. (1997) Unique monocyte subset in patients with AIDS dementia. Lancet 349:692-5 |
| Pulliam, L; Clarke, J A; McGrath, M S et al. (1996) Monokine products as predictors of AIDS dementia. AIDS 10:1495-500 |
| Pulliam, L; Moore, D; West, D C (1995) Human cytomegalovirus induces IL-6 and TNF alpha from macrophages and microglial cells: possible role in neurotoxicity. J Neurovirol 1:219-27 |
| Pulliam, L; Clarke, J A; McGuire, D et al. (1994) Investigation of HIV-infected macrophage neurotoxin production from patients with AIDS dementia. Adv Neuroimmunol 4:195-8 |
