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Lessons from a curious virus

Research on benign foamy virus may shed light on disease, gene therapy, common lab enzyme
Dr. Maxine Linial counting virus infections in cell culture
Dr. Maxine Linial uses a counter while determining the number of viruses infecting a culture of cells. Although the foamy virus causes no symptoms in humans, it kills cells grown in the laboratory. Photo by Todd Mcnaught

Influenza virus triggers the fever and chills of the flu. A chickenpox virus infection elicits itchy red spots. Then there's foamy virus, which causes no pain but may lead to scientific gain.

Named for the appearance of infected cells grown in the laboratory, foamy viruses pose a paradox for researchers, says Dr. Maxine Linial, a Basic Sciences investigator who has studied this little-known virus for much of the past decade.

"When foamy viruses infect certain types of cells grown in cultures, they are extremely cytopathic (damaging to cells) and cause cell death," she said. "Yet animals and humans infected with the virus don't appear to be compromised in any way, despite the fact that infection persists throughout the life of the animal and that foamy viruses infect many different cell types within the body."

While foamy viruses may have no known disease-causing claim to fame, Linial speculates their benign nature could teach scientists much about the tricks used by their close viral relatives to plague man and beast with illness.

Vehicle for gene therapy?

The curious virus has also spawned interest among scientists for its potential use as a vehicle for gene therapy and as a source of an enzyme commonly used in molecular biology laboratories.

Foamy viruses are members of a viral family known as retroviruses, which includes such heavy-hitting pathogens as HIV, which causes AIDS, and several viruses that cause tumors in humans and animals. Subtypes of foamy viruses naturally infect many vertebrate animals, including household cats, horses and all nonhuman primates. Humans can acquire the virus, which causes no symptoms, from animal bites. The first infected human was identified in 1971 in Kenya.

Although viruses are thought by many to be synonymous with disease, examples of viral infections that go unnoticed are not uncommon, Linial said.

"We're probably exposed to numerous viruses over the course of our lifetimes, but many of them cause subclinical infections with no obvious symptoms," she said.

In fact, these microscopic parasites actually benefit by causing minimal destruction to their hosts.

"For a virus to be successful, it needs to be able to multiply and spread to other organisms," she said. "A virus that kills its host soon after infection is at a survival disadvantage."

By those standards, foamy viruses have reached the pinnacle of success. Like all retroviruses, foamy viruses cause persistent, lifelong infections because a hallmark of their parasitic behavior is to weave their genetic material permanently into the chromosomes of their hosts. They're also remarkably adept at hitchhiking from one unsuspecting animal to another. While saliva is suspected as a likely transmission route, exactly how the virus infects a new host is unclear.

A split personality

To spread, retroviruses must emerge from their dormant state in a host cell's DNA and reproduce, or replicate. That's an aspect of foamy virus behavior that's especially intriguing, Linial said.

"When foamy virus replicates, it kills cells," she said. "Studies from nonhuman primates have demonstrated foamy virus in all parts of the animal's tissue, yet the virus only replicates in vivo in cells that line the oral cavity, perhaps in what are known as mucosal epithelial cells."

These cells normally have a high turnover in the body and would suffer few consequences by viral killing.

"The question our lab has tried to address is, how does the virus shut off its ability to multiply in other cell types?"

Recent studies from Linial's laboratory, led by former graduate student Chris Meiering, may shed some light on foamy virus' split personality.

Foamy virus genetic material contains two control regions that govern whether the virus lies dormant in the host chromosome or kicks into its multiplication cycle. Meiering demonstrated in laboratory cultures of human cells that a foamy virus regulator protein, known as Tas, binds to and activates both control regions during replication, but only to one when the virus is dormant. More recently, he discovered that a protein unique to foamy viruses, called Bet, can block viruses that have been triggered to multiply.

Complexity in simple virus

Linial speculates that Bet serves as a fail-safe mechanism to keep the virus from replicating under conditions in which it might be tempted to do so. Yet to be determined are the signals from the host that modulate the activity of Bet and Tas.

Such regulation seems enormously complex for a rather simple virus, Linial said.

"Foamy virus is somewhat like Epstein-Barr virus (EBV), which is associated with mononucleosis and lymphoma, in that EBV is typically latent in B cells and only occasionally does it replicate," she said. "But EBV has 200 genes to do what foamy virus does with only five genes."

Despite its simple structure, some foamy virus attributes may prove to have useful applications in the clinic and in the laboratory. Like its close relative, HIV, foamy virus has been explored as a potential delivery vehicle, or vector, for gene therapy to treat human disease. Because retroviruses infect nondividing cells-and many desirable targets of gene therapy are nondividing cells such as blood-forming stem cells-scientists are eager to adapt such viruses for therapeutic use. Linial said that even though HIV vectors would be stripped of their disease-causing genes before use, there is enough stigma associated with this virus to make the benign foamy viruses much more attractive.

Active enzyme

Foamy viruses also possess a unique version of an enzyme, known as reverse transcriptase, which is much more active than that found in other retroviruses. Reverse transcriptase is used by such viruses to copy RNA into DNA, which retroviruses must accomplish prior to stitching their genetic material into that of their host. Commercially available preparations of reverse transcriptase are commonly used in molecular biology laboratories for routine genetic experiments.

"Foamy viruses contain many fewer molecules of reverse transcriptase than other retroviruses," Linial said. "Each foamy virus enzyme has to do the work of 50. Carolyn Stenbak, a grad student in the lab, has found that the foamy virus enzyme is much more active than those commonly used today."

The highly active foamy virus enzyme could prove to be more useful in the laboratory than other forms now available for purchase. Fred Hutchinson, in conjunction with the National Cancer Institute, where collaborators on this project work, has filed for patent protection on the enzyme, which is available for licensing.

While commercial or therapeutic applications may draw attention to the foamy virus, its basic biology continues to intrigue Linial.

"These are viruses that are remarkably well-adapted to their hosts," she said. "If we can understand how they accomplish this, we may be able to find new strategies to combat more pathogenic viruses."

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