Epstein–Barr virus (EBV) is a human tumor virus and a model of herpesviral latency. The virus efficiently infects resting human B lymphocytes and induces their continuous proliferation in vitro, which mimics certain aspects of EBV’s oncogenic potential in vivo. How lymphoblastoid cell lines (LCLs) evolve from the infected lymphocytes is uncertain. We conducted a systematic time-resolved longitudinal study of cellular functions and transcriptional profiles of newly infected naïve primary B lymphocytes. EBV reprograms the cells comprehensively and globally. Rapid and extensive transcriptional changes occur within 24 h and precede any metabolic and phenotypic changes. Within 72 h, the virus activates the cells, changes their phenotypes with respect to cell size, RNA, and protein content, and induces metabolic pathways to cope with the increased demand for energy, supporting an efficient cell cycle entry on day 3 postinfection. The transcriptional program that EBV initiates consists of 3 waves of clearly discernable clusters of cellular genes that peak on day 2, 3, or 4 and regulate RNA synthesis, metabolic pathways, and cell division, respectively. Upon onset of cell doublings on day 4, the cellular transcriptome appears to be completely reprogrammed to support the proliferating cells, but 3 additional clusters of EBV-regulated genes fine-tune cell signaling, migration, and immune response pathways, eventually. Our study reveals that more than 11,000 genes are regulated upon EBV infection as naïve B cells exit quiescence to enter a germinal center-like differentiation program, which culminates in immortalized, proliferating cells that partially resemble plasmablasts and early plasma cells.

Epstein-Barr virus (EBV) has established lifelong infection in more than 90% of humanity. While infection is usually controlled by the immune system, the human host fails to completely eliminate the pathogen. Several herpesviral proteins are known to act as immunoevasins, preventing or reducing recognition of EBV-infected cells. Only recently were microRNAs of EBV identified to reduce immune recognition further. This Gem summarizes what we know about immunomodulatory microRNAs of herpesviruses.

Epstein-Barr virus (EBV) is a model of herpesvirus latency and epigenetic changes. The virus preferentially infects human B-lymphocytes (and also other cell types) but does not turn them straight into virus factories. Instead, it establishes a strictly latent infection in them and concomitantly induces the activation and proliferation of infected B cells. How the virus establishes latency in its target cells is only partially understood, but its latent state has been studied intensively by many. During latency, several copies of the viral genome are maintained as minichromosomes in the nucleus. In latently infected cells, most viral genes are epigenetically repressed by cellular chromatin constituents and DNA methylation, but certain EBV genes are spared and remain expressed to support the latent state of the virus in its host cell. Latency is not a dead end, but the virus can escape from this state and reactivate. Reactivation is a coordinated process that requires the removal of repressive chromatin components and a gain in accessibility for viral and cellular factors and machines to support the entire transcriptional program of EBV’s ensuing lytic phase. We have a detailed picture of the initiating events of EBV’s lytic phase, which are orchestrated by a single viral protein – BZLF1. Its induced expression can lead to the expression of all lytic viral proteins, but initially it fosters the non-licensed amplification of viral DNA that is incorporated into preformed capsids. In the virions, the viral DNA is free of histones and lacks methylated cytosine residues which are lost during lytic DNA amplification. This review provides an overview of EBV’s dynamic epigenetic changes, which are an integral part of its ingenious lifestyle in human host cells.