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

Cinzia Giagulli,Ekta Manocha,Arnaldo Caruso,Riccardo Dolcetti,Alessandro Orro,Alberto Zani,Simone Zorzan,Federica Filippini,Francesca Caccuri,Antonella Bugatti,Pasqualina D’Ursi

doi:10.1038/s41417-020-00246-9

Abstract

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.

Highlights

Combined antiretroviral therapy has dramatically slowed HIV-1 disease progression in seropositive individuals, improving their survival and contributing to a decline of AIDS-related mortality [1]
We investigated the biologic effects of the refp17 and two clonogenic vp17s isolated from lymphoma patients, non‐Hodgkin lymphoma (NHL)-a101 and NHL-a102, which belong to two different categories of vp17s presenting aa insertions at position 117–118 and 125–126, respectively [12]
We explored the molecular mechanisms through which vp17s promote B-cell proliferation and demonstrated that the clonogenic activity of these variants is triggered by protease-activated receptor 1 (PAR1)-mediated epidermal growth factor receptor (EGFR) transactivation through G proteins of the Gq family and a matrix metalloproteases (MMPs)-dependent process

Summary

Introduction

Combined antiretroviral therapy (cART) has dramatically slowed HIV-1 disease progression in seropositive individuals, improving their survival and contributing to a decline of AIDS-related mortality [1]. Different mechanisms have been hypothesized for B-cell transformation in HIV+ patients, including the pathogenic involvement of HIV-1 structural and regulatory proteins, such as gp120 and Tat, which induce chronic inflammation and B-cell activation and proliferation [3, 4]. Unlike the wild-type protein (refp; derived from HIV BH10, Clade B), vp17s isolated from blood and lymphoma tissues of NHL patients were shown to directly stimulate B-cell proliferation by activating the oncogenic PI3K/Akt signaling pathway [12]. These NHL-derived vp17s are characterized by amino acid (aa) insertions in the C-terminus at position 117–118 (Ala–Ala) or 125–126 (Gly–Asn) and by other mutations throughout the sequence. Ultra-deep pyrosequencing showed that these two categories of vp17s are more frequently detected in plasma of HIV+ patients with NHL than those not showing evidence of lymphoma [12]

Methods

Results

Conclusion