       Document 0397
 DOCN  M9640397
 TI    Neurotoxicity of the human immunodeficiency virus type 1 tat
       transactivator to PC12 cells requires the Tat amino acid 49-58 basic
       domain.
 DT    9604
 AU    Weeks BS; Lieberman DM; Johnson B; Roque E; Green M; Loewenstein P;
       Oldfield EH; Kleinman HK; Laboratory of Developmental Biology, National
       Institute of Dental; Research, National Institutes of Health, Bethesda,
       MD 20892, USA.
 SO    J Neurosci Res. 1995 Sep 1;42(1):34-40. Unique Identifier : AIDSLINE
       MED/96058753
 AB    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)
 DE    Acquired Immunodeficiency Syndrome  Amino Acids/*TOXICITY  Animal
       Caudate Nucleus/*DRUG EFFECTS  Dose-Response Relationship, Drug  Human
       *HIV-1  Peptides/*TOXICITY  Putamen/*DRUG EFFECTS  PC12 Cells  Rats
       Time Factors  Trans-Activators  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

