Investigators Uncover a New Approach to Target Herpesviruses
A new study has uncovered how cytomegalovirus can bypass the body’s defense mechanisms that prevent viral infections.
Individuals infected with cytomegalovirus (CMV), a virus from the herpes family, typically do not show signs of symptoms, but for individuals with weakened immune systems and unborn infants, the virus can cause serious health issues, such as birth defects and transplant failures.
The US Centers for Disease Control and Prevention estimates that 1 in 3 infants are already infected with CMV by age 5 and over 50% of adults have been infected with CMV by age 40. Once CMV is in a person’s body it can stay for life and reactivate. Additionally, a person can be re-infected with different strains of the virus.
As CMV has evolved, the virus has found a way to bypass the body’s defense mechanisms that usually protect against viral infections and, until now, investigators have been unable to determine how.
In a new study published in PNAS, however, investigators have uncovered the mechanism that allows the CMV virus to replicate, a finding that could help create new opportunities for therapies to treat CMV and other viruses.
Typically, the cell blocks the DNA from the virus when it enters the cell, rendering the virus unable to act and multiply. In observing CMV, the investigators noticed that CMV carries viral DNA into the cell along with proteins called PP71. CMV then releases PP71 which enables the virus to replicate and the infection to spread through the cell.
However, PP71 has a short life span, and the proteins die after a few hours, which is not enough time to create a virus, presenting a missing link—how is the virus able to multiply after the PP71 proteins have died?
The investigators discovered that PP71 activates another protein, IE1, within the first few hours of entering the cell, and the IE1 protein takes over after PP71 dies.
In order to confirm these findings, the investigators created a synthetic version of CMV and adjusted the levels of IE1 proteins, allowing the virus to infect the cell while controlling the amount of time that the IE1 protein would break down in the cell.
“We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently,” Noam Vardi, PhD, a postdoctoral scholar and first author of the study, said in a recent statement. “But if the protein breaks down faster, the virus can’t multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate.”
The study could have implications that are applicable to improving understanding of other viruses, according to the investigators, particularly when it comes to the question of how cells are able to maintain their identity over time.
One example pertains to how stem cells choose a path based on the proteins that surround them during development. After the proteins disappear, the cells do not change, so the stem cells that turn into neurons continue to be neurons long after those proteins are gone.
“The issue is similar for the virus,” Leor S. Weinberger, PhD, William and Ute Bowes Distinguished Professor and director of Gladstone—University of California San Francisco Center for Cell Circuitry expressed in the statement. “It was not clear what mechanisms allowed the virus to continue replicating long after the initial signal from the PP71 had decayed to a whisper. Our findings uncover a circuit encoded by the virus that controls its fate and indicate that such circuits may be quite common in viruses.”
The new study could lead to a therapeutic target for cytomegalovirus and other herpesviruses, such as Epstein-Barr virus, which causes mononucleosis, and herpes simplex virus 1 and 2, which are responsible for most cold sores as well as genital herpes.