HIV-1 transactivator protein Tat induces proliferation and TGF beta expression in human articular chondrocytes

Abstract

Abstract. The human immunodeficiency virus-1 (HIV-1) protein Tat binds to cell surface antigens and can regulate cellular responses. Tat has similar immunosuppressive effects as transforming growth factor-/3 (TGFfl) and both inhibit lymphocyte proliferation. TGFfl is expressed by primary human articular chondrocytes and is their most potent growth factor. The present study analyzed the interactions of TGFfl and HIV Tat in the regulation of human articular chondrocytes. Synthetic or recombinant full-length Tat (1-86) induced chondrocyte proliferation and this was of similar magnitude as the response to TGF/L Tat peptides that did not contain the RGD motif had similar chondrocyte stimulatory activity as full-length Tat. Among a series of Tat peptides, peptide 38-62 which contains the basic domain was the only one active, suggesting that this region is responsible for the effects on chondrocyte proliferation. Full-length Tat and peptide 38-62 synergized with TGF~ and induced proliferative responses that were greater than those obtained with any combination of the known chondrocyte growth factors. Further characterization of the interactions between Tat and TGF/~ showed that Tat increased synthesis and TGFfl activity and TGF/~I mRNA levels. The stimulatory effects of Tat and peptide 38-62 on chondrocyte proliferation were reduced by neutralizing antibodies to TGFfl and by TGF~ antisense oligonucleotides. These results identify a virally 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 TGFfl.

HIV-Tat promotes cellular proliferation and inhibits NGF-induced differentiation through mechanisms involving Id1 regulation

“…Earlier studies report that Tat, a potent stimulator of the cellular neurotoxic proteins such as TNFa gene (Sastry et al, 1990;Chen et al, 1997), exhibits the ability to cause neuronal cell damage and apoptosis through mechanisms that are independent of TNFa pathway (Merrill et al, 1992;Chen et al, 1997;Shi et al, 1998). In addition to its proapoptotic properties, an increasing number of reports ascribed a role for Tat in enhancing cell proliferation (Lotz et al, 1994;Cantaluppi et al, 2001). The complex relationship between neuronal signaling and neuronal damage induced by HIV-1 prompted us to investigate the participation of Tat in the NGF/TrkA signaling pathways.…”

“…One of the viral proteins that strongly affect neuronal survival and function is Tat, which is expressed at an early stage of viral infection and plays a pivotal role in transcriptional activation of HIV-1-LTR (Gaynor, 1995). By interacting with different host proteins, Tat has been shown to promote survival and proliferation in various cell types (Ensoli et al, 1993;Zauli et al, 1993Zauli et al, , 1995Lotz et al, 1994;Seve et al, 1999;Cantaluppi et al, 2001), and in some cases promote apoptosis (Nath et al, 1996;Kruman et al, 1998). There is a growing line of evidence supporting the functional crosstalk between nerve growth factor (NGF) action and HIV-1 infection.…”

Growth factor responsiveness of human articular chondrocytes in aging and development

“…Chondrocytes were isolated as previously described (8). Briefly, cartilage slices were removed from the femoral condyles and tibial plateaus and washed in Dulbecco's modified Eagle's medium (DMEM).…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…HIV tat protein has been linked to high TGF-b secretion in infected cells Zauli et al 1992;Lotz et al 1994;Sawaya et al 1998;Reinhold et al 1999). The association of viral gp160 with CD4 on monocytes can also induce TGF-b production (Hu et al 1996).…”