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Journal of Neuroscience, Vol 16, 2546-2552, Copyright © 1996 by Society for Neuroscience
Extracellular human immunodeficiency virus type 1 Tat protein promotes aggregation and adhesion of cerebellar neurons
MJ Orsini, CM Debouck, CL Webb and PG Lysko
Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
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 proteins containing
mutations in the Arg-Gly-Asp (RGD) cell adhesion motif or a deletion of the
cysteine-rich domain had no effect on neuronal morphology. In contrast, a
Tat protein that contained a deletion of the proline-rich domain promoted
neuronal aggregation. Aggregation of neurons was inhibited by the addition
of monoclonal antibodies directed against the RGD and basic domains of Tat,
but not against the proline-rich 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 basic domains similar to HIV-1 Tat, induced aggregation
and acted as a substrate for adhesion when added at higher concentrations
than HIV-1 Tat. Vitronectin, fibronectin, and RGD- containing peptides did
not induce morphological changes in neurons or act as substrates for
adhesion. The ability of Tat to induce morphological changes and promote
adhesion was independent of the ability of Tat to transactivate HIV gene
expression. Our results suggest that extracellular Tat protein most likely
alters neuronal morphology and mediates adhesion by acting in a manner
similar to an extracellular matrix protein.
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