Identifying the mechanisms that determine CMV latency could lead to targeted therapies that prevent CMV-related disease.
TUCSON, Ariz. – University of Arizona researchers have found genes within the human cytomegalovirus (CMV) that control whether it remains latent (inactive) or actively replicates (multiplies). The discovery could lead to targeted therapies that prevent disease caused by reactivation of the virus, which nearly everyone carries.
Most people are infected with CMV early in life and have no symptoms or even knowledge of the infection. The virus remains in the body in a latent state that can later reactivate, causing life-threatening problems in people with compromised immune systems. Further, a baby infected prior to birth can have devastating birth defects.
Felicia Goodrum, PhD, associate professor in the UA College of Medicine – Tucson Department of Immunobiology and UA Department of Molecular and Cellular Biology and a member of the UA BIO5 Institute, researches the latency of CMV. In two recent papers – one a spotlight article – in the Journal of Virology, Dr. Goodrum details her laboratory’s discovery of genes within CMV that promote either latency or reactivation and replication of the virus.
“Viral latency is one of the most poorly understood phenomena in virology,” she says. “This work defines a basic molecular switch, controlling entry into and exit from latency. Therefore, for the first time, we have identified targets that may allow us to control virus reactivation.”
CMV is one of eight human herpesviruses, infecting 60-99 percent of adults worldwide. Among the extremely common herpesviruses are those that cause chicken-pox, shingles and mononucleosis, in addition to herpes simplex.
“Most people carry three to four herpesviruses most of the time without knowing it,” Dr. Goodrum says. “People know viruses like influenza better because they get sick. After you recover from the flu, your relationship with that virus is essentially over. But with a latent virus, you have it forever. There are absolutely no symptoms of CMV and no way to cure the virus. This is an exceptionally stealthy virus.”
Though typically latent, CMV can cause significant health problems when reactivated.
When an infected person has a compromised immune system, like in cases of organ or stem cell transplant, HIV infection and some intensive chemotherapy regimens in cancer patients, the virus can cause life-threatening disease. The virus also is the leading cause of infectious disease-related birth defects, affecting more babies in the United States than Downs Syndrome, fetal alcohol syndrome and spina bifida.
CMV is the largest known human virus, with about 200 genes, and in an effort to understand its unusual persistence, Dr. Goodrum is studying the genetics of the virus, mutating different regions of the genome to identify ones that impact latency. In one particular region of CMV’s genetic code, she has identified separate genes that are encoded to either promote or inhibit viral function.
“We don’t know exactly how these are functioning yet. We’re trying to identify the pathways in the infected cells that they are targeting. We think they’re targeting the same cellular pathways, but with opposing effects. It’s the balance of these actions that we think eventually dictates a latent or a productive infection,” she says.
There is no vaccine for CMV and the only drugs existing currently target cells that are actively replicating the virus, leaving the latent cells untouched. Identifying the mechanisms that determine latency could lead to targeted therapies that prevent CMV-related disease.
“Treatments could either force the virus to reactivate and then clear it out, or prevent reactivation all together,” Dr. Goodrum says. “Those would be huge medical successes.”
Dr. Goodrum’s second paper, co-authored with Jeremy P. Kamil, PhD, assistant professor, Department of Microbiology & Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center in Shreveport, discusses the complex interactions between the genes that promote latency or replication, suggesting there’s a particular threshold that determines how the virus behaves.
“We think the virus is always percolating up, testing the waters so to speak, and if the conditions are right it will begin replicating,” Dr. Goodrum says.
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In addition to corresponding author Dr. Goodrum, UA researchers who contributed to the study, “Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection,” included Mahadevaiah Umashankar, PhD, UA BIO5 Institute; Michael Rak, UA BIO5 Institute and UA College of Medicine – Tucson Department of Cellular and Molecular Medicine; Farah Bughio, UA Department of Cellular and Molecular Medicine; Patricia Zagallo, UA Department of Immunobiology; and Katie Caviness, UA Graduate Interdisciplinary Program in Genetics.
In addition to Dr. Goodrum and corresponding author Dr. Kamil, researchers who contributed to the study, “An Epistatic Relationship Between the Viral Protein Kinase UL97 and the UL133-UL138 Latency Locus During the Human Cytomegalovirus Lytic Cycle,” included Gang Li and Christopher C. Nguyen, Department of Microbiology and Immunology and Center for Molecular and Tumor Virology, LSU Health Sciences Center Shreveport; Michael Rak, UA Department of Cellular and Molecular Medicine; and Mahadevaiah Umashankar, PhD, UA BIO5 Institute.
This work was supported by a grant from the National Institutes of Health (National Institute of Allergy and Infectious Diseases, AI079059, and National Cancer Institute, CA343111) and the Pew Scholars in Biomedical Science Award.
Media Contact: Jean Spinelli, 520-626-2531