How Old Viruses May Haunt Us - Research History

•IN THE LAB
•APRIL 12, 2011

Scientists Study Interplay Between Retroviral Genes and Cancer, Other Diseases

By AMY DOCKSER MARCUS

The human genome is littered with the genetic remains of ancient viruses that once infected people but now lie dormant. Until recently, scientists didn’t believe they played a role in modern disease.

New research is causing many scientists to think again. Recent studies suggest these old virus shards may play a role in Hodgkin’s lymphoma, multiple sclerosis, rheumatoid arthritis and other diseases.

The ancient viruses scientists are most interested in date from waves of infections that took place as recently as 100,000 to 200,000 years ago. In modern humans, the genes were most likely inherited from a common ancestor infected with retroviruses, probably from rodents. Unlike other kinds of viruses, retroviruses copy their own genes into a host’s DNA. Some of the retroviruses are believed to have infected sperm cells and eggs, ensuring the virus would be passed from generation to generation in the genome.
Researchers estimate that 8% of the human genome consists of virus genes and their remains, translating into approximately 80,000 genes scattered in an individual’s DNA. That’s about twice as many as the number of genes that determine a person’s height, eye color, hair color and other characteristics, says John M. Coffin, a retrovirologist at Tufts University, who is studying these ancient virus genes. “There is more virus in us than there is us in us,” he says.

Animal species including mice have ancient retrovirus genes implicated in diseases. It wasn’t until 2003, when the human genome was published, that researchers realized humans have old virus genes, too. The emergence of huge databases containing gene sequences from animals and humans allowed researchers to start mining for possible connections between old viruses and present-day diseases.

The trouble seems to start when the old retrovirus genes—broken down and disabled over time, and silent in healthy people—are hijacked, turned on again or put to a new use. “Retroviruses inserting themselves into our genome—or hijacking copies of other genes to insert in our genome—wreak havoc,” says Stephen Tapscott of the Fred Hutchinson Cancer Research Center, part of a team that published a paper last year on the link between the ancient process and why some people get a common type of muscular dystrophy.

Not all retrovirus remnants do bad things. Scientists believe a gene from a very old retrovirus played a role in the formation of the placenta. Some speculate that incorporating different parts of old infections into the human genome helped prevent infection by related viruses.

In healthy people, one particular ancient retrovirus is barely detectable, but in HIV patients who also have lymphoma, the virus is found in high levels. The researchers think in some patients, HIV stirs things up, “turning on DNA that in healthy people is usually dormant,” says Mark Kaplan of the University of Michigan, who has been studying the old viruses in people with HIV and HIV lymphoma.

Something similar may be happening in Hodgkin’s lymphoma. Stephan Mathas and Constanze Bonifer lead a team of researchers who looked in cell lines and tissue samples of cancer patients and found parts of an ancient retrovirus were activated. The old virus gene in turn activated a gene that stimulates cancer growth and is critical to cancer cells’ survival, says Dr. Bonifer, professor of experimental hematology at the University of Leeds in the U.K. and co-author of a study last year.

Dr. Bonifer says the researchers now are trying to identify other retroviral genes that may be activated in Hogkin’s lymphoma and other cancers. It is possible that cancers are more aggressive if more retroviral genes are activated, she says; a therapy turning off the retroviral genes might inhibit cancer growth.

Brigitte Huber, a professor of pathology at Tufts University School of Medicine, and a team of researchers showed that Epstein-Barr virus and two herpes viruses can activate an old retrovirus gene. One theory the researchers plan to test in mice is whether chronic, low-level reactivation of the retrovirus plays a role in developing multiple sclerosis.

A study is testing a similar idea in patients with chronic fatigue syndrome. The researchers are collecting blood samples at six-month intervals from people who had mononucleosis, including those who later developed chronic fatigue syndrome and those who didn’t. The researchers will see if the old retrovirus gene is activated in those who developed chronic fatigue syndrome compared with those who didn’t. If a connection is demonstrated, therapies could be developed to turn off the old retrovirus gene. “The idea is that if you don’t have chronic stimulation then the symptoms would go away,” Dr. Huber says.

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