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Hanging Around With Epstein-Barr

Scientists think they know why infection with the virus is a life-long affair

FRIDAY, March 29, 2002 (HealthDayNews) -- You could call Epstein-Barr Virus the "Thing That Wouldn't Leave."

Now scientists have a better idea why it's such a persistent guest.

When it's a new infection, the herpes-like microbe causes mononucleosis. The virus then lingers in the body in a latent state forever. But in some people, for reasons that aren't clear, it can eventually trigger cancers such as Hodgkin's disease, Burkitt's lymphoma, and throat and nose tumors. It has also been implicated in other tumors, including breast cancer, but that link is not yet proven.

How EBV, as the virtually omnipresent germ is abbreviated, manages to live beneath the body's defense radar has been a mystery. But Pennsylvania scientists say they've found that stretches of genetic material on the virus' donut-shaped genetic structure -- called a plasmid -- appear to shield it from destruction in the cells it inhabits.

Those stretches closely mimic patches of human DNA called telomeres, which hold together the ends of gene-bearing chromosomes.

The Pennsylvania researchers' discovery, appearing in the March issue of Molecular Cell, could one day aid scientists hoping to treat cancer-causing viruses. It could also help scientists craft better delivery systems, or vectors, for gene therapies.

The new research was conducted by Paul Lieberman and his colleagues at the Wistar Institute, a world-famous virus lab in Philadelphia.

Researchers have known that for EBV to survive in cells, it needs the aid of a protein called EBNA1. This protein binds to the virus and assembles the cellular machinery needed to copy the virus' genetic code when cells replicate on their own. In that way, EBV manages to perpetuate stable versions of itself into successive generations of cells.

Cells have several enzymes that cruise the nucleus in search of DNA damage. The ends of chromosomes are protected from the repair enzymes by telomeres, which serve the same function as shoelace tips. Without telomere-like shells, chromosomes would become dangerously unstable, because the repair enzymes could fuse two separate chromosomes together.

In true parasite fashion, EBV gets the same tune-up service for free, Lieberman's group found.

As the plasmid -- the virus' donut-shaped genetic structure -- lies dormant in the nucleus, its telomere-like DNA is a-whirl with attention from the maintenance enzymes, which dutifully keep the strands intact and ready for replication.

"It was a surprising but interesting finding that this circular virus, which exists like a small chromosome in the nucleus, uses a very similar mechanism as the linear chromosome uses to maintain the stability of its genome," Lieberman says. "The viruses are extremely sophisticated and are tapped into that mechanism. They're not seen as a foreign piece of DNA."

The finding, which applies to all herpes viruses, may prove clinically useful. While "a little bit speculative" at this point, Lieberman says, it appears that the maintenance enzymes may be vulnerable to suppression by small molecule drugs. "The trick will be to find out which enzyme will get rid of the virus but not kill the cell," he adds.

Dr. Bill Sugden, an EBV expert at the University of Wisconsin's McArdle Laboratory for Cancer Research, calls the latest findings "fascinating," and says the work could have important implications for gene therapy.

Since EBV infection is apparently for life, researchers are now trying to convert the virus' loitering nature into a force for cure by stitching therapeutic genes into the plasmid's own genetic code.

"Other viral vectors elicit a massive immune response, but in theory [EBV shouldn't] elicit a massive immune response," Sugden says.

One ideal disease candidate for such an approach is cystic fibrosis, the deadly respiratory illness. If a neutralized EBV ring could be rigged with the right corrective gene and introduced into a patient, doctors might have a safe long-term treatment for the disorder.

What to Do: To find out more about Epstein-Barr Virus, visit the University of Rochester, or the U.S. Centers for Disease Control and Prevention.

SOURCES: Paul Lieberman, Ph.D., associate professor, Wistar Institute, Philadelphia; Bill Sugden, Ph.D., professor of oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison; March 2002 Molecular Cell
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