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The Journal of Neuroscience, September 10, 2003, 23(23):8417-8422

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BRIEF COMMUNICATION
Synaptic Transport of Human Immunodeficiency Virus-Tat Protein Causes Neurotoxicity and Gliosis in Rat Brain

Annadora J. Bruce-Keller,¹ Ashok Chauhan,² Filomena O. Dimayuga,¹ Jillian Gee,¹ Jeffrey N. Keller,¹ and Avindra Nath²

¹Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and ²Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287

Neurodegeneration, synaptic alterations, and gliosis are prominent features of human immunodeficiency virus (HIV) encephalitis, but HIV encephalitis is distinct from other viral encephalitides because neurodegeneration occurs in uninfected neurons at anatomical sites that are often distant from the site of viral replication. The HIV protein Tat is both neurotoxic and proinflammatory; however, its contribution to HIV-related synaptic dysfunction remains unknown. To determine the consequences of continuous Tat production in brain, we genetically engineered rat C6 glioma cells to stably produce Tat and stereotaxically infused these cells into the rat striatum or hippocampus. We discovered that HIV-Tat protein could be transported along anatomical pathways from the dentate gyrus to the CA3/4 region and from the striatum to the substantia nigra, resulting in behavioral abnormalities, neurotoxicity, and reactive gliosis. This demonstrates a unique neuronal transport property of a viral protein and establishes a mechanism for neuroglial dysfunction at sites distant from that of viral replication. Tat may thus be an important participant in brain dysfunction in HIV dementia.

Key words: AIDS dementia; basal ganglia; hippocampus; inflammation; neurodegeneration; synaptic transport

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Received March 17, 2003; revised July 24, 2003; accepted July 29, 2003.

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