Synaptic transport of human immunodeficiency virus-Tat protein causes neurotoxicity and gliosis in rat brain.
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.
Bruce-Keller
Annadora J
AJ
Department of Anatomy and Neurobiology, MN 222 Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0298, USA. abruce@uky.edu
Chauhan
Ashok
A
Dimayuga
Filomena O
FO
Gee
Jillian
J
Keller
Jeffrey N
JN
Nath
Avindra
A
D015526:AIDS Dementia Complex / Q000209:etiology; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D018014:Gene Transfer Techniques; D005910:Glioma / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009368:Neoplasm Transplantation; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques; D013378:Substantia Nigra / Q000473:pathology; D013569:Synapses / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus