HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT ACTIVITY IN HUMAN NEURONAL CELLS - UPTAKE AND TRANSACTIVATION

Neurological dysfunction in AIDS occurs in the absence of productive i nfection of neurons, and may involve modulation of neuronal cell funct ion by viral or cellular products released from surrounding infected c ells. The human immunodeficiency virus type 1 (HIV-1) transactivator p rotein Tat may be one such factor, as it can act as a neurotoxin, indu ces marked morphological changes in neurons and astrocytes in primary embryonic rodent brain cultures, and is released by certain HIV-1-infe cted cells. In addition, Tat can alter expression of cellular genes in several non-neuronal cell types. To explore the possibility that Tat may also mediate neuronal dysfunction in AIDS through non-lethal effec ts on neurons, we determined the trans-activating ability of Tat in hu man neuronal cells. We generated human neuronal cell lines stably expr essing several HIV-I rat genes, and also tested human neuronal cells e xposed to extracellular recombinant Tat protein. Both endogenously exp ressed Tat as well as exogenous recombinant Tat protein up-regulated H IV-1 long terminal region (LTR)-driven gene expression by several hund red-fold. Only brief exposure to recombinant Tat was necessary and no toxic effects were seen at levels sufficient for trans-activation. Fur thermore, Tat significantly enhanced virus expression in neuronal cell s transfected with molecular clones of HIV-1. These results show that Tat is trans-activationally active in human neuronal cells, and can be taken up from the extracellular compartment by these cells in a biolo gically active form. Neurons represent an important potential target f or Tat-mediated cellular dysfunction.