02/28/2024
Common herpesvirus hijacks cellular proteins to establish a lifelong presence
New research published in PNAS uncovered how human cytomegalovirus, or CMV, uses cellular proteins to become dormant in blood cells. This research, conducted in the laboratory of Christine O'Connor, PhD, identifies a potential vulnerability that could be exploited for therapeutic interventions.
CMV is an extremely common virus that infects an estimated 90% of the world's population. The infection is lifelong because, like other herpes viruses, CMV persists indefinitely in our cells as it hides from our immune system. However, immune dysregulation in patients undergoing immunosuppression for organ transplantation, for example, results in CMV reactivating from its dormant (or latent) state. This can cause serious illness in these patients, sometimes leading to mortality.
"Current antivirals for CMV target a stage of the virus lifecycle that follows viral reactivation, when disease is already primed to occur," says Dr. O'Connor, Associate Staff in Infection Biology. "One approach to mitigating viral-associated disease is to prevent viral reactivation from occurring."
Dr. O'Connor received $4.6 million from the National Institutes of Health in 2021 to investigate how the virus becomes latent and later reactivates during times of immune dysregulation. The current study's first author, Ian Groves, PhD, Project Staff, spearheaded the research project to identify which proteins in our own cells are involved in the process.
The team found that the cellular protein called CTCF binds sequences within the virus genome and reshapes the virus's DNA. The CTCF protein helps regulate the genes our cells express under certain conditions, Dr. O'Connor explains. To do this, CTCF molds our DNA to form and maintain specific 3D structures, influencing whether a gene is turned "on" or "off." During the latent stage of CMV infection, CTCF binds the virus DNA and changes its shape, forming a loop. This loop formation sequesters a critical driver of active virus replication. CTCF helps the virus remain dormant, and the immune system can no longer detect the virus.
Now that the team has proof the virus uses CTCF to help CMV remain dormant, they can justify looking at ways to exploit the process to treat CMV infection. Dr. O'Connor, Dr. Groves, and the rest of the team are now working to understand how CTCF is evicted from the virus DNA, allowing the virus to reactivate.
"Our findings are a step forward in understanding how CMV is able to quiesce in certain blood cells," says Dr. Groves. "This discovery could aid the path forward in developing novel therapeutics, and the possibilities are exciting."
