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

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. What's new? Although it is well established that individuals afflicted with HIV infection are at risk to develop Hodgkin as well as Non-Hodgkin lymphoma, the exact molecular relationship between HIV and a frequently co-infecting oncogenic -herpesvirus, Epstein Barr Virus (EBV), remains unclear. Here the authors provide evidence that by up-regulating the chemokine receptor CXCR2, EBV renders B lymphocytes permissive to the growth-promoting effects of the HIV matrix protein p17, especially a natural variant called S75X. p17 binding to CXCR2 in turn upregulates the expression of the EBV-encoded oncogene LMP-1 promoting the proliferation of EBV-infected B cells and demonstrating a bidirectional molecular interplay between HIV p17 and EBV LMP-1 proteins in the development of EBV-driven lymphomas during HIV infection.