Caught sleeping: Study captures virus dormant in human cells

Cytomegalovirus, hidden in most people, begins to give up secrets of its stealth

Princeton scientists have taken an important step toward understanding a virus that infects and lies dormant in most people, but emerges as a serious illness in transplant patients, some newborns and other people with weakened immune systems.

The virus, called human cytomegalovirus, enters the bone marrow and can hide there for a lifetime. Until now, however, scientists had not been able to study the virus in its latent stage because it infects only humans and does not readily infect or become dormant in laboratory strains of bone marrow cells.

In a study published online Nov. 27, Felicia Goodrum, a postdoctoral fellow, and Tom Shenk, a professor of molecular biology, demonstrated a laboratory system for studying the virus in its latent stage. They showed they could establish a latent infection in freshly collected bone marrow cells and then retrigger an active infection. They drew on their system to discover a set of genes that the virus uses in its latent state and that may give the virus its great capacity for stealth.

Knowing what genes the virus uses to hide and re-emerge could give pharmaceutical companies targets for designing drugs that disrupt those mechanisms. “So you could dream that some day in the future we could clear the virus from a person and not just treat the symptoms that occur when the virus re-emerges,” said Shenk.

Cytomegalovirus is in a broad family of herpes-related viruses, which includes the virus that causes chicken pox and shingles. The only treatment doctors currently have for cytomegalovirus is an antiviral drug called gancyclovir, which stops the virus from replicating during its active infection phase, but has no effect during the latent stage, when the virus does not replicate.

Another possible use for the research would be to develop a diagnostic test that indicates when the virus is likely to reactivate itself. If scientists could pinpoint genes that turn on just in advance of reactivation, then doctors could use that information in deciding whether to administer antiviral drugs to their patients. Currently, doctors prescribe gancyclovir preemptively for many patients, even though it has significant side effects.

The researchers described their results in an online edition of the Proceedings of the National Academy of Sciences. It is scheduled to appear in the journal’s Dec. 10 print edition. Goodrum and Shenk collaborated with Craig Jordan of the University of Kentucky Medical Center and Kevin High of the Wake Forest University School of Medicine, who supplied human bone marrow cells and expertise in working with them.

The key to the study’s success, said Shenk, was Goodrum’s painstaking work in learning to handle freshly harvested bone marrow cells in the lab and to maintain them in a state that matches as closely as possible their condition in the human body. Her supply of cells was limited because they are badly needed for bone marrow transplantations. Goodrum could use only cells that were caught in a filter used in transplant procedures.

Shenk said her work makes it possible to answer big questions that have long eluded researchers. It is unknown, for example, what specific cells the virus infects among the many constituents of bone marrow. In their study, Goodrum narrowed the search to a group of cells that constitute just 1 percent of bone marrow cells. The next step, said Goodrum, will be to look at even smaller subpopulations of cells and compare the activity of the virus and its genes in each of them.

“We’d like to know the answers to some very basic questions,” said Goodrum. “How many copies of the virus are there in an infected cell? And how exactly do they get passed along?”

“These are all things you get to think about when you have a model system,” said Shenk. “You couldn’t do it without the system Felicia developed.”

Understanding the virus is important because roughly half of all organ or bone marrow transplant patients, who are always given immune-suppressing drugs, experience some complication with cytomegalovirus, said Shenk. Women who become infected or experience a reactivation during a pregnancy risk passing the virus to the fetus, which can lead to birth defects, including deafness and developmental disorders.

Between 50 and 85 percent of Americans become infected with cytomegalovirus by age 40, according to the National Institutes of Health. Shenk said he believes the figure may be even higher, because every sample Goodrum has studied had at least some cells that were infected with the virus.