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A natural HIV p17 protein variant up‐regulates the LMP‐1 EBV oncoprotein and promotes the growth of EBV‐infected B‐lymphocytes: Implications for EBV‐driven lymphomagenesis in the HIV setting
Author(s) -
Martorelli Debora,
Muraro Elena,
Mastorci Katy,
Dal Col Jessica,
Faè Damiana Antonia,
Furlan Chiara,
Giagulli Cinzia,
Caccuri Francesca,
Rusnati Marco,
Fiorentini Simona,
Carbone Antonino,
Caruso Arnaldo,
Dolcetti Riccardo
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29494
Subject(s) - virology , epstein–barr virus , gammaherpesvirinae , biology , human immunodeficiency virus (hiv) , virus , immunology , cancer research , viral disease , herpesviridae
Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein–Barr virus (EBV)‐infected primary and fully transformed B‐lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B‐lymphocytes or the ectopic expression of the latent membrane protein‐1 viral oncoprotein in EBV‐negative B‐cells up‐regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV‐infected primary B‐cells more efficiently bind and internalize p17 proteins as compared with activated B‐lymphocytes. The S75X variant bound more efficiently to EBV‐infected primary and fully transformed B‐lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up‐regulation and increased interleukin‐6 production. Notably, the S75X variant markedly up‐regulated latent membrane protein‐1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV + B‐cell growth promotion. These results indicate that EBV infection sensitizes B‐lymphocytes to CXCR2‐mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV‐driven lymphomagenesis in the human immunodeficiency virus setting.