UA Researchers Create First `Roadmap’ to Understand Ability of Herpesvirus to Remain Dormant in Humans to Attack Another Day

A collaborative team of UA researchers have created an in-depth model of the human cytomegalovirus during its sleep-like state in dormancy to better understand how the virus can lie dormant and then reactivate and pose life-threatening disease risk.

Researchers at the University of Arizona Health Sciences are the first to develop a “roadmap” of the dormant stage of the human cytomegalovirus, a member of the herpesvirus family, which includes viruses, or agents of infection, that cause chickenpox, herpes simplex and mononucleosis.

These viruses can remain dormant in a sleep-like state within the body over a long period, residing in cells without causing detectable damage or illness, waiting to activate later.

The research team seeks to understand the ability of complex, submicroscopic disease-causing DNA viruses to survive and evade detection and to provide a path toward developing therapies that can control the ability of the virus to move from a sleep-like state to activation.

“We now have an unprecedented look at the virus in dormancy that provides new targets to study to develop novel medications targeting the existing, but not yet activated, infection,” said Felicia Goodrum, PhD, associate professor at the UA College of Medicine – Tucson, Department of Immunobiology. “Importantly, many genes identified by this study do not have well-understood functions in infection. Therefore, this study provides an initial road map to advance our understanding of HCMV latency and persistence.”

The UA research team includes members from the UA BIO5 Institute, the Graduate Interdisciplinary Program in Genetics, the UA Department of Immunobiology and the UA Center on Aging. The study, “Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency,” was published in the Proceedings of the National Academy of Sciences of the Unites States of American (PNAS), in November.

Nine herpesviruses are known to infect humans. Cytomegalovirus (CMV) is a herpesvirus that has infected 50–99 percent of the human population worldwide and approximately 60–70 percent of the U.S. population.

CMV infections are chronic and may have few symptoms at first, followed by a time of undetected infection during which the virus lives within cells without causing noticeable damage or illness.

When CMV is reactivated, it can cause life-threatening disease risks in people with compromised immune systems, including organ or stem cell transplant recipients, as well as AIDS and cancer patients undergoing intensive chemotherapy. A major health concern in children, CMV infection is the leading cause of birth defects, affecting 1 in 150 live births in the United States. It can lead to hearing loss and other illnesses as severe as cerebral palsy, seizure disorders and even death.

Currently, no vaccine is available for infected individuals.

Because the virus is maintained at low levels in a healthy human host, it rarely is detected. Therefore, the UA research team began its investigation by enriching the RNA sequences of the virus to detect them above the vast number of human sequences. By enriching the RNA sequences, the research team was able to define the CMV transcriptome (the entire collection of RNA sequences in a cell) in the context of natural infection, in both an experimental model of dormancy and in the cells of infected individuals without symptoms. By analyzing the transcriptome, researchers can determine when and where each gene is turned on or off in the cells and tissues of an organism.

This process allowed the team to see what genes were expressed and how these changed if the virus was in a replicative-versus-latent state, important steps to understand viral dormancy (or latency) in the host. The team identified 141 genes that were similarly expressed in experimental and natural infection, more than previously thought. Researchers also identified genes that are differently regulated during dormant and active states, making them candidates as key regulators controlling the switch between dormancy and reactivation.

“Understanding the patterns of viral gene expression associated with CMV dormancy is an important goal toward defining the molecular underpinnings of this sleep-like state and its associated health risks,” said Dr. Goodrum, who also is a member of the UA BIO5 Institute.

About the University of Arizona Health Sciences

The University of Arizona Health Sciences is the statewide leader in biomedical research and health professions training. The UA Health Sciences includes the UA Colleges of Medicine (Phoenix and Tucson), Nursing, Pharmacy and Mel and Enid Zuckerman College of Public Health, with main campus locations in Tucson and the growing Phoenix Biomedical Campus in downtown Phoenix. From these vantage points, the UA Health Sciences reaches across the state of Arizona and the greater Southwest to provide cutting-edge health education, research, patient care and community outreach services. A major economic engine, the UA Health Sciences employs almost 5,000 people, has nearly 1,000 faculty members and garners more than $126 million in research grants and contracts annually. For more information: uahs.arizona.edu (Follow us: Facebook | Twitter | YouTube | LinkedIn)