EXTRACELLULAR HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT PROTEIN PROMOTES AGGREGATION AND ADHESION OF CEREBELLAR NEURONS

Recombinant human immunodeficiency virus (HIV-1) Tat protein added to the culture medium of rat cerebellar neurons promoted aggregation and formation of spoke-like neurites in a dose-dependent manner. Tat prote ins containing mutations in the Arg-Gly-Asp (RGD) cell adhesion motif or a deletion of the cysteine-rich domain had no effect on neuronal mo rphology. In contrast, a Tat protein that contained a deletion of the proline-rich domain promoted neuronal aggregation. Aggregation of neur ons was inhibited by the addition of monoclonal antibodies directed ag ainst the RGD and basic domains of Tat, but not against the proline-ri ch domain. The same domains of Tat required to induce aggregation also mediated adhesion of neurons to Tat-coated substrates. The HIV-2 Tat protein, which lacks an RGD sequence but contains cysteine-rich and ba sic domains similar to HIV-1 Tat, induced aggregation and acted as a s ubstrate for adhesion when added at higher concentrations than HIV-1 T at. Vitronectin, fibronectin, and RGD-containing peptides did not indu ce morphological changes in neurons or act as substrates for adhesion. The ability of Tat to induce morphological changes and promote adhesi on was independent of the ability of Tat to transactivate HIV gene exp ression. Our results suggest that extracellular Tat protein most likel y alters neuronal morphology and mediates adhesion by acting in a mann er similar to an extracellular matrix protein.