Mechanism Found for Long-Term Survival of EBV

In a finding that could potentially guide development of new treatments for cancers associated with the Epstein-Barr virus (EBV), a study from The Wistar Institute (Philadelphia PA, USA) reveals the unexpected mechanism that allows the EBV to survive dormant inside its host for so long.

Usually the virus causes no symptoms, but occasionally latent EBV reactivates and contributes to certain human cancers, among them Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease. The study, appearing in the March 2002 issue of Molecular Cell, describes how the EBV genome uses a system of cellular proteins similar to the proteins at the ends of human chromosomes called telomeres. In both the virus genome and the human chromosome, these proteins are critical to preserving genome integrity and, therefore, survival. When the researchers inhibited the telomeric protein complexes associated with the EBV, the latent virus genome became unstable and was eventually lost from the cell. The finding was particularly surprising because the structure of the virus genome is circular while the human genome is linear.

"It turns out that it doesn't matter whether the proteins bind to the end of a linear chromosome or exist independently on a circular chromosome--the basic function is the same,” says study senior author Dr. Paul M. Lieberman. "Those telomeric proteins are telling the cell not to destroy the viral DNA, and biologically, that's very interesting.”

The new study was based on the knowledge that EBV survival required the presence of a viral protein called EBNA1 that binds to the viral site where DNA replication begins and signals the cellular machinery to replicate the viral genome at the precise moment that the cellular genome replicates. The researchers speculated that EBNA1 did not work alone, however. Rather, they believed that it worked with one or more cellular proteins to initiate viral DNA replication and ensure its maintenance.

Using biochemical methods of DNA affinity purification coupled with mass spectroscopy, the group succeeded in identifying three proteins involved in the process: a protein called Telomeric Repeat Binding Factor 2 (TRF2); a TRF2-interacting protein known as hRap1; and telomere-associated poly-ADP ribose polymerase, or Tankyrase. Dr. Lieberman's group went on to show that these telomere-binding proteins interact with EBNA1 and are required for the virus to maintain its DNA and survive during latency. Mutations to these proteins, experiments showed, led to the loss of the latent viral genome, since the virus could no longer survive in the host cell.

In addition to the biological significance of the findings, there may be medical implications, as well, Dr. Lieberman notes. "In malignancies where EBV is known to be a contributing agent, inactivating the mechanism by which the virus maintains its genome could inhibit tumor cell growth. Such a therapeutic approach might also be effective against EBV and other related members of the herpes virus family, although this remains to be shown.”




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