The proposed studies are based upon the observation that, although human immunodeficiency virus Type 1 (HIV) penetrates the brain early in disease, only in a subset of patients with advanced immunosuppression do inflammatory monocytes enter the brain in large numbers and result in neurological dysfunction. The underlying hypothesis is that brain microvascular endothelial cells (BMVECs) facilitate monocyte entry following direct HIV infection, up-regulation of adhesion molecules, or macrophage-mediated disruption of blood-brain barrier function (BBB). In previous studies the Investigator and his associates demonstrated that pro-inflammatory cytokines and other immunoregulatory molecules produced by macrophages disrupt BBB function and produce up-regulation of adhesion molecules on BMVECs. This provides one mechanism for transendothelial passage of virus and inflammatory cells across the BBB. The Investigator speculates that during advanced immunosuppression, immune competent macrophages can disrupt BBB function and permit passage of monocytes into brain. In addition, he proposes that specific viral strains facilitate neuroimmune activation and attendant monocyte recruitment/binding to endothelial cells, disruption of the BBB, and passage of inflammatory cells into the CNS. In this application the Investigator proposes to assay virus-endothelial cell infection and its relationship to BBB function. The researchers will use monocytes from HIV-infected patients with/without HIV dementia to determine if such cells have facilitated transendothelial migration. They will analyze several putative neurotoxins, as well as other potential agents isolated by RP-HPLC, to determine which factors might facilitate monocyte migration through BMVEC. Their recently-developed SCID mouse model of HIV encephalitis will be used to assess endothelial- and chemokine-mediated monocyte recruitment into the CNS. The combined efforts are designed to determine the viral and immune determinants for BBB dysfunction in AIDS, information that could be helpful in adapting strategies to prevent migration of monocytes into the brain during HIV dementia.
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