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Regular Articles |
§
From the Center for Neurovirology and Neurodegenerative
Disorders,*
the Departments of Pathology and Microbiology
and
Medicine,
and the Eppley
Institute for Cancer and Allied Diseases,§
University of Nebraska Medical Center, Omaha, Nebraska; the Division of
Infectious Diseases,¶
Childrens Hospital Los
Angeles, University of Southern California School of Medicine, Los
Angeles, California; the Reed Neurology Research
Institute,||
University of California Los Angeles School
of Medicine, Los Angeles, California; and the Department of
Surgery,**
University of Arizona School of
Medicine, Tucson, Arizona
The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the 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-brain barrier (BBB), we performed cross-validating laboratory, animal model, and human brain tissue investigations into HAD pathogenesis. First, an artificial BBB was constructed in which human brain microvascular endothelial and glial cells—astrocytes, microglia, and/or monocyte-derived macrophages (MDM)—were placed on opposite sides of a matrix-coated porous membrane. Second, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis, activation of microglia, virus infection, monocyte brain infiltration, and ß-chemokine expression. The results, taken together, showed that HIV-1-infected 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 marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE, microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration, and ß-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of ß-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces ß-chemokine-mediated monocyte migration in HAD.
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