HIV-1 TRANSACTIVATOR PROTEIN TAT INDUCES PROLIFERATION AND TGF-BETA EXPRESSION IN HUMAN ARTICULAR CHONDROCYTES

The human immunodeficiency virus-1 (HIV-1) protein Tat binds to cell s urface antigens and can regulate cellular responses. Tat has similar i mmunosuppressive effects as transforming growth factor-beta (TGFbeta) and both inhibit lymphocyte proliferation. TGFbeta is expressed by pri mary human articular chondrocytes and is their most potent growth fact or. The present study analyzed the interactions of TGFbeta and HIV Tat in the regulation of human articular chondrocytes. Synthetic or recom binant full-length Tat (1-86) induced chondrocyte proliferation and th is was of similar magnitude as the response to TGFbeta. Tat peptides t hat did not contain the RGD motif had similar chondrocyte stimulatory activity as full-length Tat. Among a series of Tat peptides, peptide 3 8-62 which contains the basic domain was the only one active, suggesti ng that this region is responsible for the effects on chondrocyte prol iferation. Full-length Tat and peptide 38-62 synergized with TGFbeta a nd induced proliferative responses that were greater than those obtain ed with any combination of the known chondrocyte growth factors. Furth er characterization of the interactions between Tat and TGFbeta showed that Tat increased synthesis and TGFbeta activity and TGFbeta1 mRNA l evels. The stimulatory effects of Tat and peptide 38-62 on chondrocyte proliferation were reduced by neutralizing antibodies to TGFbeta and by TGFbeta antisense oligonucleotides. These results identify a virall y encoded protein and a synthetic peptide derived from it as novel and potent chondrocyte growth stimuli which act at least in part through the induction of TGFbeta.