SAN DIEGO—Researchers at the University of California, San Diego (UC San Diego) School of Medicine have discovered that the human protein CPEB1 is crucial in the progress of cytomegalovirus (CMV), opening the door for new therapeutic interventions. In a study recently published in Nature Structural and Molecular Biology, scientists identified what they feel is a clear link between CMV and CPEB1.
“We found that CPEB1, one of a family of hundreds of RNA-binding proteins in the human genome, is important for establishing productive cytomegalovirus infections,” said senior author Dr. Gene Yeo, professor of cellular and molecular medicine at UC San Diego School of Medicine.
According to the U.S. Centers for Disease Control and Prevention, CMV is a common virus that infects people of all ages. Over half of adults by age 40 have been infected with CMV, and once it is in a person’s body, it stays there for life and can reactivate. Most people infected with CMV show no signs or symptoms. However, CMV infection can cause serious health problems for people with weakened immune systems such as from organ and bone marrow transplants, and people infected with human immunodeficiency virus (HIV), as well as babies infected with the virus before they are born, known as congenital CMV.
Yeo’s team discovered that CPEB1 levels increase dramatically in human cells infected by CMV. Using genomics technologies, the researchers also found that increased CPEB1 levels in CMV-infected cells leads to the abnormal processing of RNAs encoding thousands of human genes. In addition, they were surprised to find that CPEB1 was necessary for proper processing of viral RNAs. Without the host CPEB1 protein, viral RNA did not mature properly and the virus was weakened.
“The discovery that a single RNA binding protein encoded in the host genome was responsible for the vast majority of the host and viral RNA processing changes was a result of trying to understand the basic biology underlying host-virus responses in at the gene expression level,” says Yeo. “We were very surprised to find that we were able to pinpoint the changes to one gene, particularly one that binds directly to RNA. We were fortunate that the CPEB1 protein, when depleted, results in decreased virus production.”
Once infected by CMV, cells undergo abnormal changes, thereby increasing production of the virus and spreading infection to more cells. In collaboration with Dr. Deborah Spector, Distinguished Professor at UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences, the team went on to show that suppressing CPEB1 levels during CMV infection reversed these harmful cellular changes and reduced viral production tenfold.
“CPEB1 was previously shown to play a role in neuronal development and function, but this involvement in active viral infections is unexpected,” noted first author Dr. Ranjan Batra, a postdoctoral fellow in Yeo’s lab. “This discovery has important implications for many viral infections.”
The next step for this research is to determine the therapeutic value of inhibiting CPEB1 in CMV infections and identify other RNA-binding proteins that may be important in other viral infections, such as herpes viruses. While a vaccine is not imminent from this research, it does provide a potential path to treatment once infection has occurred in unvaccinated conditions.
According to Yeo, “There is a strong sense of urgency to get a vaccine to market, as CMV is the largest cause of birth defects. It has been estimated that the direct economic costs of CMV infection exceeds $2 billion annually. The market [for a vaccine] could exceed $1 billion annually.”
The study was funded in part by the National Institutes of Health, California Institute of Regenerative Medicine, National Science Foundation, Myotonic Dystrophy Foundation and Alfred P. Sloan Foundation.
