222 HIV-1 p17 Activates PTEN and Inhibits Akt Signaling Pathway in B Cells: Evidence for a Variant with Different Effects on Signaling and Cell Growth

Abstract

The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment as a virokine to deregulate several immune functions, through a specific interaction with a cellular surface receptor (p17R). At the moment signal transduction pathways triggered by p17/p17R interaction are not completely characterized yet. In this study we map the structure-function relationship of p17, analyzing the specific signal transduction pathways induced by different functional epitopes involved in p17/p17R interaction. We demonstrate that p17 displays two distinct functional epitopes involved in p17R binding capable of selectively activating or deactivating a variety of signalling pathways. In particular, we show that p17 induces a transient activation of the transcriptional factor AP-1 in Raji cells and it upregulates MAPK/ERK and downregulates PI3K/AKT signal cascades, which are the major intracellular signalling pathways involved in AP-1 activation and in cellular functions such as cell growth, survival and tumourigenesis. Our data also demonstrate that the effect of p17 on AKT signaling is due to its capability to keep PTEN, a phosphatase that regulates the PI3-K/AKT pathway, in an active state through the Ser/Thr kinase ROCK, recently reported to control PTEN activity. Moreover, we show that among the different p17 variants one named S75X triggers, on contrary to p17, an activation of PI3K/Akt signalling pathway and a consequent increase of cell proliferation which could be correlate with the development of a large fraction of human cancers in HIV+ patients. In summary, this study demonstrates the complexity of p17 binding to and signalling through its receptor, and suggests that a conformational change of the protein due to specific escape mutations may play an important role in receptor binding, signaling and cell growth.