HIV-1 p17 Activates PTEN and Inhibits Akt Signalling Pathway in B Cells: Evidence for a p17 Variant with Opposite Effects

The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH2-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyzed the signal transduction pathways induced by p17 and p17 variants upon interaction with p17R interaction on Raji B cells by Western blot and EMSA. Data obtained showed that p17 was able to induce a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2, and downregulate pAkt expression, which are the major intracellular signalling components involved in AP-1 activation. These effects were mediated by the C-terminal region of p17, which displayed the ability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the Ser/Thr kinase ROCK. Indeed, a C-terminal truncated form of p17 (p17delta36) was capable of inducing activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we showed that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggered an activation of PI3K/Akt signalling pathway, and led to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the C-terminal region in modulating the p17 signalling pathways, highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant displaying the power of promoting B cell growth and tumorigenesis.