Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis

The numbers of immune-activated brain mononuclear phagocytes (MPs) affect t he progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate, in measure, from a pool of circulating monocytes . To address the mechanism(s) for monocyte penetration across the blood-bra in barrier (BBB), we performed cross-validating laboratory, animal model, a nd human brain tissue investigations into HAD pathogenesis. First, an artif icial BBB was constructed in which human brain microvascular endothelial an d glial cells-astrocytes, microglia, and/or monocyte-derived macrophages (M DM)-were placed on opposite sides of a matrix-coated porous membrane. Secon d, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyse s of human HIVE tissue defined the relationships between astrogliosis, acti vation of microglia, virus infection, monocyte brain infiltration, and beta -chemokine expression. The results, taken together, showed that HIV-1-infec ted microglia increased monocyte migration through an artificial BBB 2 to 3 .5 times more than replicate numbers of MDM, In the HIVE SCID mice, a marke d accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE, microglial activation acid vir us infection correlated with astrogliosis, monocyte transendothelial migrat ion, and beta-chemokine expression, Pure cultures of virus-infected and act ivated microglia or astrocytes exposed to microglial conditioned media prod uced significant quantities of beta-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces b eta-chemokine-mediated monocyte migration in HAD.