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The discovery opens the way to measure levels of the latent virus in people who donate blood and tissue and organs, which could help reduce the risk of disease in transplant recipients, said Edward S. Mocarski, lead author of the report, which appears in the Oct. 1 Proceedings of the National Academy of Sciences.
It also gives investigators a tool for developing a vaccine against the ubiquitous virus, said Mocarski, professor and chair of microbiology and immunology at Stanford University School of Medicine.
"This usually innocuous virus resides in some of the most important cells in the human body -- granulocyte-macrophage progenitors (GM-Ps), the parents of important white cells crucial to the immune response," said Mocarski. "We had suspected that white-cell precursors would be involved, but no one had any understanding of what genes CMV might produce in the latent period there."
CMV is a member of the ancient and complex herpes virus family. It infects nearly 100 percent of some populations worldwide, transmitted before or at birth and later through saliva, blood, urine and sexual contact.
The initial infection causes only mild symptoms, and afterwards the virus remains latent and harmless in most people with healthy immune systems, said Mocarski. "But it can cause birth defects in a developing fetus and can cause life-threatening disease in children and adults with weakened immune systems, such as people with AIDS, premature infants and organ transplant recipients."
Latency is one of the strategies that have helped herpes viruses persist for millions of years -- and for the lifetimes of infected individuals. CMV causes little disease as long as the host remains healthy. When the host's immune system is immature or compromised, however, the balance is disturbed. CMV is reactivated, and causes a range of diseases that can lead to death.
Antiviral drugs can slow, but not completely prevent, damage from the reactivated virus, said Mocarski.
The process of latency and how the sleeping CMV is reawakened has long baffled scientists, Mocarski said. Antibody tests can identify people who are infected but cannot gauge the amount of latent virus in the body. And CMV studies are complicated by the genetic complexity of the virus. Compared with simpler viruses that have as few as three genes, CMV's genome is huge: It consists of 230 genes.
"The large genome and the large number of genes carried by CMV, combined with the complexity of cell types that might be involved in acute and in latent infection, presented formidable obstacles to understanding the biology of this virus," Mocarski said.
Part of the problem facing researchers is that during latency, genes responsible for the virus' growth shut down.
To find the genes that remain active during the latent period, the Stanford researchers infected a mixture of GM- P-type cells in a test tube. "We found that these cells were able to carry the viral genome without being damaged themselves, and we detected unique genes that were active then," Mocarski said.
They next used the identification of those unique genes -- called CMV latency-associated transcripts (CLTs) -- to explore the infection in a natural state. Their goal was to try to discover the type of cells in which latent CMV hides.
Working with the Stanford Hospital Bone Marrow Transplantation Program, the researchers obtained tiny samples of leftover bone marrow from donors who had provided tissue for marrow transplants. The researchers didn't know whether any given donor was infected with CMV. After isolating the white-cell progenitors, they used specialized probes to see whether the CLTs were present, indicating a natural, latent infection.
The researchers discovered this latent infection marker in five out of seven marrow samples from individuals infected with CMV.
"This provided further evidence that the genes we had discovered were bona fide, because they appeared in a naturally occurring latent infection," Mocarski said. "It also provided evidence that white-cell progenitors can be a major source of reactivated CMV, which can lead to disease in transplant recipients," he said.
Because of the difficulty of finding tissue that won't be rejected by a would-be transplant recipient's immune system, clinicians sometimes knowingly use tissue infected with CMV.
But now that clinicians can measure the quantity of latent CMV in tissues, they might begin to exclude donors with the highest levels of infection and thereby reduce the risk of severe CMV disease in recipients, Mocarski said. Also, knowing the level of infection in the donor tissue will help clinicians more effectively protect the recipients against CMV disease, possibly through the use of antiviral drugs, he added.
Mocarski, an expert in the biology and genetics of human herpes viruses, has been investigating the molecular biology of cytomegalovirus and the genes involved in its latency for 20 years.
Other researchers, who worked on the study at Stanford, include Dr. Kazuhiro Kondo, now an associate professor at Osaka University Medical School; Jiake Xu, a postdoctoral fellow in Mocarski's laboratory; and Dr. Karl Blume, professor of medicine and director of the Stanford Hospital Bone Marrow Transplantation Program.
The research was funded in part by the National Institute of Allergy and Infectious Diseases and SmithKline Beecham.
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CONTACT: Stanford Medical Center Rosanne Spector, 415/725-5374 or 415/723-6911
(media contact) manishmaleland.stanford.edu. M.A. Malone, 415/723-6912 or 415/723-6911
(for broadcast media) mamaloneleland.stanford.edu. Edward S. Mocarski, 415/723-6435
(for comment) mocarskileland.Stanford.edu.
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