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

The HIV-1 matrix protein p17 is a structural protein thatcan act in the extracellular environment to deregulate severalfunctions of immune cells, through the interaction of itsNH2-terminal region with a cellular surface receptor (p17R).The intracellular events triggered by p17/p17R interactionhave been not completely characterized yet. In this study weanalyzed the signal transduction pathways induced by p17 andp17 variants upon interaction with p17R interaction on RajiB cells by Western blot and EMSA. Data obtained showedthat p17 was able to induce a transient activation of the transcriptionalfactor AP-1. Moreover, it was found to upregulatepERK1/2, and downregulate pAkt expression, which are themajor intracellular signalling components involved in AP-1activation. These effects were mediated by the C-terminalregion of p17, which displayed the ability of keeping PTEN, aphosphatase that regulates the PI3K/Akt pathway, in an activestate through the Ser/Thr kinase ROCK. Indeed, a C-terminaltruncated form of p17 (p17delta36) was capable of inducingactivation of the PI3K/Akt pathway by maintaining PTEN inan inactive phosphorylated form. Interestingly, we showedthat among different p17s, a variant derived from a UgandanHIV-1 strain, named S75X, triggered an activation of PI3K/Akt signalling pathway, and led to an increased B cell proliferationand malignant transformation. In summary, this studyshows the role of the C-terminal region in modulating thep17 signalling pathways, highlighting the complexity of p17binding to and signalling through its receptor(s). Moreover,it provides the first evidence on the presence of a p17 naturalvariant displaying the power of promoting B cell growth andtumorigenesis.