B-cell clonogenic activity of HIV-1 p17 variants is driven by PAR1-mediated EGF transactivation


C. Giagulli, F. Caccuri, S. Zorzan, A. Bugatti, A. Zani, F. Filippini, E. Manocha, P. D’Ursi, A. Orro, R. Dolcetti, and A. Caruso


Cancer Gene Therapy, doi:10.1038/s41417-020-00246-9, 2020


Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV+ individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV+ patients.



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