Overview on Epstein-Barr Virus-Host Interactions With a Focus on Host Cell Transcriptome Alterations.

The Epstein-Barr virus (EBV) belongs to the gamma subgroup of human herpesviruses. EBV is particularly lymphotropic regarding its latency, meaning that it preferentially targets lymphocytes as its immunological niche. During the establishment of the complex virus-host relationships, the virus influences the human host cell transcriptome inducing changes in RNA quantity and quality aided by a multitude of virally encoded molecules such as microRNAs, lncRNAs, peptides, and proteins. Quantitative changes in human gene expression of infected host cells are due to epigenetic mechanisms, such as altered promoter methylation patterns and altered microRNA- or lncRNA-based post-transcriptional gene regulation mechanisms. The quality of the human transcriptome is altered including changes in chemical RNA modifications and alterations in alternative splicing (AS) patterns. These molecular mechanisms contribute to the immune evasion of EBV, enhanced host cell proliferation and desensitization to apoptosis induction. These mechanisms are highly relevant to the process of malignant transformation of infected host cells, highlighting the tumorigenic potential of EBV. This review article addresses the role of AS in malignant transformation of EBV-infected host cells. For this purpose, publicly available transcriptome datasets from EBV-positive human Burkitt lymphomas (BL) were analyzed in an EBV-copy number dependent manner. We identified 14 directly dysregulated splicing factors, predominantly components of the splicing machinery as well as trans-acting splicing factors, with putative relevance for virus-mediated alterations of host cell splicing patterns.