Abstract
Epstein-Barr Virus (EBV) is a γ-herpesvirus that infects >90% of the human population. Although EBV persists in its latent form in healthy carriers, the virus is also associated with several human cancers. EBV is strongly associated with Burkitt lymphoma (BL), even though there is still no satisfactory explanation of how EBV participates in BL pathogenesis. However, new insights into the interplay between viruses and microRNAs (miRNAs) have recently been proposed. In particular, it has been shown that B-cell differentiation in EBV-positive BL is impaired at the post-transcriptional level by altered expression of hsa-miR-127. Here, we show that the overexpression of hsa-miR-127 is due to the presence of the EBV-encoded nuclear antigen 1 (EBNA1) and give evidence of a novel mechanism of direct regulation of the human miRNA by this viral product. Finally, we show that the combinatorial expression of EBNA1 and hsa-miR-127 affects the expression of master B-cell regulators in human memory B cells, confirming the scenario previously observed in EBV-positive BL primary tumors and cell lines. A good understanding of these mechanisms will help to clarify the complex regulatory networks between host and pathogen, and favor the design of more specific treatments for EBV-associated malignancies.
Highlights
The herpesviruses represent a very large, clearly defined group of viruses of considerable medical importance and uniqueness.Epstein-Barr virus (EBV) is the best-known and most widely studied member, due to its clinical and oncogenic importance.[1]Following primary infection, Epstein-Barr Virus (EBV) preferentially infectsB-lymphocytes and establishes a persistent infection, which is maintained throughout the host’s lifetime
The differential expression of this miRNA in distinct B-cell subsets strongly suggests its significant role in the B-cell differentiation program, and that the physiological regulation of hsa-miR-127 in B cells might pass through B-cell receptor (BCR) signaling, as only full induction with F(ab’)[2] directed against the BCR is able to downregulate its expression.[12]
To ascertain whether hsa-miR-127 overexpression in Burkitt lymphoma (BL) is related to the presence of the virus, we focused on the EBV-encoded Epstein-Barr nuclear antigen 1 (EBNA1) protein, as this is the only viral product expressed in EBVpositive BL cells
Summary
The herpesviruses represent a very large, clearly defined group of viruses of considerable medical importance and uniqueness.Epstein-Barr virus (EBV) is the best-known and most widely studied member, due to its clinical and oncogenic importance.[1]Following primary infection, EBV preferentially infectsB-lymphocytes and establishes a persistent infection, which is maintained throughout the host’s lifetime. Epstein-Barr virus (EBV) is the best-known and most widely studied member, due to its clinical and oncogenic importance.[1]. B-lymphocytes and establishes a persistent infection, which is maintained throughout the host’s lifetime. Infection of other cell types occurs (principally epithelial cells) but is much less efficient.[2]. Primary EBV infection in vivo generally arises at an early age and is usually asymptomatic. If the infection is acquired during adolescence or later, it can result in infectious mononucleosis.[3] Of note, EBV has been implicated in the pathogenesis of an increasing number of human malignancies, including a strong association with Burkitt lymphoma (BL).[4,5,6] The World Health
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