HIV-1 transactivating factor Tat is actively released by HIV-infected cells and, in its extracellular form, it targets uninfected cells, contributing to tumorigenesis in HIV+ individuals. Heparan-sulfate proteoglycans (HSPGs) act as chemotactic receptors in B-lymphocytes and their expression increases in these cells after neoplastic transformation. Accordingly, Syndecan-1 expression has been proposed as a diagnosis marker for AIDS-related lymphomas. HSPGs are also expressed on endothelial cells (ECs), where they act as receptors for a variety of cytokines and growth factors (including Tat), regulating inflammation and tumor growth.
On these bases, here we decided to evaluate the role of HSPGs/Tat interaction in the processes of chemotaxis and extravasation of B lymphoid cells (LCs).
To this aim, we exploited Burkitt lymphoma cells overexpressing two HSPGs endowed with distinct structural/functional features: Syndecan-1 (a transmembrane receptor) and Glypican (a GPI-anchored receptor).
We thus demonstrated that both Glypican and Syndecan-1 bind Tat and mediate LC adhesion to an EC monolayer. Differently, only the transmembrane HSPG Syndecan-1, but not the GPI-anchored Glypican, mediates Tat-dependent LC chemotaxis and transendothelial migration. Then, we investigated the Syndecan-1-mediated signal transduction pathway involved in mediating these biological activities: only in Syndecan-1, but not Glypican-overexpressing LCs, Tat induces the activation of pp60src, that physically associates with Syndecan-1. In turn, pp60src activation is required for LCs chemotaxis and transmigration, as demonstrated by using specific pp60src inhibitors.
These data provide new insights about the role and mechanisms of action of Tat and HSPGs during HIV infection.