IDENTIFICATION OF A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT EPITOPE THAT IS NEUROEXCITATORY AND NEUROTOXIC

Tat is an 86- to 104-amino-acid viral protein that activates human imm unodeficiency virus type 1 expression, modifies several cellular funct ions, and causes neurotoxicity. Here, we determined the extent to whic h peptide fragments of human immunodeficiency virus type 1 BRU Tat(1-8 6) produced neurotoxicity, increased levels of intracellular calcium ( [Ca2+](i)), and affected neuronal excitability. Tat(31-61) but not Tat (48-85) dose dependently increased cytotoxicity and levels of [Ca2+](i ) in cultured human fetal brain cells. Similarly, Tat(31-61) but not T at(48-85) depolarized rat hippocampal CA1 neurons in slices of rat bra in. The neurotoxicity and increases in [Ca2+](i) could be significantl y inhibited by non-N-methyl-D-aspartate excitatory amino acid receptor antagonists. Shorter 15-mer peptides which overlapped by 10 amino aci ds each and which represented the entire sequence of Tat(1-86) failed to produce any measurable neurotoxicity. Although it remains to be det ermined if Tat acts directly on neurons and/or indirectly via glial ce lls, these findings do suggest that Tat neurotoxicity is conformationa lly dependent, that the active site resides within the first exon of T at between residues 31 to 61, and that these effects are mediated at l east in part by excitatory amino acid receptors.