MicroRNA Suppression Maintains the Latent Phase of Epstein Barr Virus Infection

A subtle interaction between viral and host enzymes keeps Epstein-Barr virus (EBV) in a latent state – safe from destruction by the immune system – until conditions favor its activation and reproduction.

Investigators at the Wistar Institute (Philadelphia, PA, USA) studied the behavior of EBV in both normal and cancerous tissues. They found that the virus produced an enzyme, BART6, which interacted with and blocked the activity of the host enzyme Dicer, which controls the synthesis of small interfering RNA (siRNA), a class of critical genome regulators. Dicer is an endoribonuclease in the RNase III family that cleaves double-stranded RNA (dsRNA) and pre-microRNA (miRNA) into short ds RNA fragments called small interfering RNA (siRNA) about 20-25 nucleotides long, usually with a two-base overhang on the 3' end.

Results published in the October 22, 2010, issue of the Journal of Biological Chemistry revealed that inhibition of Dicer blocked the production of a second viral protein, EBNA2, which would otherwise have triggered EBV reproduction. The outcome was that the virus was maintained in a latent state and it did not produce enough viral particles to trigger a response by the immune system.

At some point, if the immune system weakens due to age or a disease such as HIV/AIDS, the balance between BART6 and Dicer may be disrupted resulting in an outbreak of the virus, possibly leading to the transformation of normal cells into cancerous ones.
"Epstein-Barr infection is marked by a period of active infection and replication – the lytic stage – where it causes acute disease, but it can also remain latent, and later emerge as an effective cancer-causing agent,” said senior author Dr. Kazuko Nishikura, professor of gene expression and regulation at the Wistar Institute. "It is a strategy that allows EBV to survive our initial immune response and await conditions, such as weakened immunity, to reemerge.”

"Epstein-Barr virus uses microRNA to achieve a balance between suppressing genes and promoting genes,” said Dr. Nishikura. "This system has been so precisely tuned through evolution that BART6 only interacts with human DICER messenger RNA, which may explain why EBV does not infect other animals. Although it may be some time before we can manipulate microRNA as a part of patient care, these findings offer evidence that we may one day use some of the same tools our cells use to regulate gene activity.”

Related Links:
Wistar Institute