title: 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.
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.
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Martorelli
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Muraro
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Katy
authors.initials: K
authors.lastname: Mastorci
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dal Col
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Damiana Antonia
authors.initials: DA
authors.lastname: Faè
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.|Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Furlan
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.affiliation: Pathology Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D056742:Cyclin D2 / Q000235:genetics; D056743:Cyclin D3 / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics
chemical_list: D056742:Cyclin D2; D056743:Cyclin D3; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D015513:Oncogene Proteins; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D014763:Viral Matrix Proteins; D014764:Viral Proteins
keywords: Epstein-Barr virus; HIV p17; lymphoma