Abstract
The Epstein Barr virus (EBV) contributes to the tumor phenotype through a limited set of primarily non-coding viral RNAs, including 31 mature miRNAs. Here we investigated the impact of EBV miRNAs on remodeling the tumor cell transcriptome. Strikingly, EBV miRNAs displayed exceptionally abundant expression in primary EBV-associated Burkitt’s Lymphomas (BLs) and Gastric Carcinomas (GCs). To investigate viral miRNA targeting, we used the high-resolution approach, CLASH in GC and BL cell models. Affinity constant calculations of targeting efficacies for CLASH hits showed that viral miRNAs bind their targets more effectively than their host counterparts, as did Kaposi’s sarcoma-associated herpesvirus (KSHV) and murine gammaherpesvirus 68 (MHV68) miRNAs. Using public BL and GC RNA-seq datasets, we found that high EBV miRNA targeting efficacies translates to enhanced reduction of target expression. Pathway analysis of high efficacy EBV miRNA targets showed enrichment for innate and adaptive immune responses. Inhibition of the immune response by EBV miRNAs was functionally validated in vivo through the finding of inverse correlations between EBV miRNAs and immune cell infiltration and T-cell diversity in BL and GC datasets. Together, this study demonstrates that EBV miRNAs are potent effectors of the tumor transcriptome that play a role in suppressing host immune response.
Highlights
Burkitt’s Lymphoma and gastric cancer are both associated with Epstein Barr Virus (EBV), a prolific DNA tumor virus that latently resides in most human beings
Utilizing clinical Burkitt’s Lymphomas (BLs) and Gastric Carcinomas (GCs) datasets, we explore the roles of EBV miRNAs in primary tumors and demonstrate a role for EBV miRNAs in dampening the immune response to viral infection and oncogenesis
Applying logistic regression to each of the top 10 (BL) or 15 (GC) principal components revealed that EBV status is a major distinguishing clinical covariate in both tumor types (Figs 1A and S1), indicating that EBV is likely a key determinant in shaping the tumor transcriptome
Summary
The Epstein Barr Virus (EBV) is a ubiquitous gammaherpesvirus (γHV) that establishes lifelong infections in over 90% of the world’s population. The lytic replication program is a process utilized by all viruses to replicate and package their genetic content for spread through cell-to-cell transfer This strategy produces a large number of virions but it destroys the host cell and triggers a strong local immune response[9]. The viral latency program, the phase most closely linked with cancer, is associated with the expression of a small number of genes that support the growth and health of the infected cell[10,11,12,13,14,15,16] and by extension, the growth and health of its viral occupant In this phase of the virus infection cycle, viral and host genomes are replicated concordantly and distributed to daughter cells[17], resulting in an expansion of the infected cell population that is independent of virion production. This form of intracellular replication minimizes immune reactivity, allowing the virus to discretely double the pool of infected cells at each mitotic cycle
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