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

Debora Martorelli, Elena Muraro, Katy Mastorci, Jessica Dal Col, Damiana Antonia Faè, Chiara Furlan, Cinzia Giagulli, Francesca Caccuri, Marco Rusnati, Simona Fiorentini, Antonino Carbone, Arnaldo Caruso, Riccardo Dolcetti

Research output: Contribution to journalArticlepeer-review

Abstract

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..

Original languageEnglish
Pages (from-to)1374-1385
Number of pages12
JournalInternational Journal of Cancer
Volume137
Issue number6
DOIs
Publication statusPublished - Sep 1 2015

Keywords

  • Epstein-Barr virus
  • HIV p17
  • lymphoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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