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

Authors

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

Reference

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

Description

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.

Link

doi:10.1038/s41417-020-00246-9