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Abstract

Extracellular Tat acts as a pleiotropic molecule inducing several biological effects on different target cells. Tat stimulates the chemotaxis of numerous cell types and it appears to have oncogenic activities, including acting as a co-factor for Kaposi's sarcoma. The Tat protein has been shown to bind integrins through an RGD amino acid motif. Tat is an angiogenic factor able to induce the migration and invasion of endothelial and KS cells through the interaction of its basic domain with the VEGF receptor VEGFR2 (Flk-1/KDR). We have also found that Tat is able to mimic chemokines, activating monocyte migration through the chemokine like' cysteine-core domain. Tat is a chemoattractant for dendritic cells, and both the RGD and basic domains appear to be involved in this response. In a recent study we demonstrated that Tat is chemotactic for PMN and induces Ca2+ mobilization in vitro. Experiments using synthetic peptides showed that Tat activities on PMN are mediated by the chemokine like' region. Finally Tat is also able to induce B cell chemotaxis, while its activity on helper T cells has not yet been clarified. Here we review data on Tat-dependent chemotaxis and discuss the possible implications in Tat mediated pathogenesis.

Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms

“…Tat also transactivates several endogenous cellular genes, including cytokines, extracellular matrix proteins, and proto-oncogenes (Vene et al, 2000). Besides its nuclear localization and function, Tat protein can also be released into the extracellular environment by HIV-infected cells (Rubartelli et al, 1998).…”

“…Exogenous Tat has been suggested to have a wide range of activities due to the interaction of specific Tat domains with cellular receptors and cellular genes (Ensoli et al, 1993;Frankel and Pabo, 1988). Extracellular Tat activities seem to mediate the majority of Tat effects in vivo and are implicated in the pathogenesis of HIV-related diseases (Vene et al, 2000). Transgenic approaches provided evidence that there is a correlation between Tat protein expression and the insurgence of a variety of AIDS-related neoplasms including Kaposi's sarcoma (KS) and NHLs (Vogel et al, 1988;Corallini et al, 1993;Kundu et al, 1999).…”

All-Round Manipulation of the Actin Cytoskeleton by HIV

“…Tat consistently downregulates multiple actin regulatory proteins including cofilin and gelsolin [ 180 ], whereas it increases RhoA activity by upregulating several of its upstream activators [ 187 ]. Together, these changes lead to an aberrant increase in F-actin content that in T-cells translates into impaired chemotaxis and cell migration [ 187 , 228 ]. Interruption of chemotaxis likely increases local viral spread within lymphoid tissue, as commonly observed in AIDS patients.…”

“…In monocytes, Tat induced integrin expression [ 251 , 252 ], and increased adhesion to the extracellular matrix and endothelium [ 251 , 253 , 254 ], as well as transendothelial migration [ 254 , 255 ]. Soluble Tat also induced thin actin-rich membrane protrusions [ 251 ], and promoted chemotaxis of monocytes, neutrophils and macrophages [ 228 , 254 , 256 ]. Note that increased tissue infiltration and impaired phagocytosis in both macrophages and monocytes have been observed in HIV+ patients in vivo, and this is associated with various aspects of disease [ 257 ].…”