Neurotoxicity of the human immunodeficiency virus type 1 tat transactivator to PC12 cells requires the Tat amino acid 49-58 basic domain.
The acquired immunodeficiency syndrome (AIDS) frequently involves the central nervous system (CNS) and manifests as dementia due to encephalitis or diffuse neurodegeneration. Human immunodeficiency virus type 1 (HIV-1) proteins, potentially transported into the CNS by mononuclear inflammatory cells, have been implicated in the etiology of this HIV-1 associated neurological dysfunction. Here we investigate the neurotoxicity of the essential HIV-1 regulator protein Tat in vivo after microinfusion into the rat brain and in vitro using PC12, NG108-15, and GT17 neuronal cell lines. Infusion of either chemically synthesized Tat (Tat86) or recombinant Tat (rTat) into the striatal gray matter in Sprague-Dawley rats resulted in postural deviation ipsilateral to the infusion, a clinical presentation in rats associated with complete striatal dysfunction. Histologic examination 3 days after infusion revealed massive necrosis in the area of the distribution of the infusion. Infusion of heat denatured rTat, peptide Tat49-58, or peptide Tat57-86 did not result in clinically or histologically detectable brain damage. After 3 days incubation in vitro, the lethal dose for half (LD50) of PC12 cells due to rTat was 5 micrograms/ml. The LD50 for Tat86 under the same conditions was 10 micrograms/ml. Tat49-58 and Tat57-86 peptides were not toxic in vitro even at 10-fold higher doses. At 5 micrograms/ml, rTat was toxic to 100% of GT17 cells after 24 hr. At 5 micrograms/ml, Tat86 was toxic to 90% of the NG108-15 cells after 7 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892, USA.
B S
BS
Weeks
D M
DM
Lieberman
B
B
Johnson
E
E
Roque
M
M
Green
P
P
Loewenstein
E H
EH
Oldfield
H K
HK
Kleinman
D000163:Acquired Immunodeficiency Syndrome; D000596:Amino Acids / Q000633:toxicity*; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015497:HIV-1; D006801:Humans; D016716:PC12 Cells; D010455:Peptides / Q000633:toxicity*; D011699:Putamen / Q000187:drug effects*; D051381:Rats; D013997:Time Factors; D015534:Trans-Activators
D000596:Amino Acids; D010455:Peptides; D015534:Trans-Activators