A team from the University of Pittsburgh School of Medicine and the La Jolla Institute for Immunology has uncovered how human cytomegalovirus (CMV), a ubiquitous member of the herpesvirus family, bypasses the immune system to infect cells lining the blood vessels. The discovery, published in Nature Microbiology, identifies a molecular complex, coined GATE, that enables CMV to “sneak through a side door” into endothelial cells and potentially evade immune surveillance.
“If we don’t know what weapons the enemy is using, it is hard to protect against it,” said senior author Jeremy Kamil, PhD, associate professor at Pitt. “We found a missing puzzle piece that represents one possible reason why immunization efforts against CMV have been unsuccessful.”
A key player in birth defects and vascular damage
CMV is the leading infectious cause of birth defects in the United States. It infects most adults without symptoms but can have devastating effects during pregnancy and in immunocompromised individuals, including transplant recipients. Despite its prevalence and clinical burden, vaccine development for CMV has so far failed.
In approximately one in every 200 babies born with congenital CMV, one in five experiences hearing loss or other long-term health issues. “The lack of an effective vaccine remains a major public health challenge,” said the study authors.
What is GATE and why does it matter?
Herpesviruses typically use a protein complex involving glycoprotein H (gH) and glycoprotein L (gL) to enter cells. However, the researchers found that CMV forms an alternate complex involving gH, UL116, and UL141, termed the GATE complex, which allows the virus to bypass this typical route and infect endothelial cells via an entirely different mechanism.
According to the study, “gH/gL complexes are targets of neutralizing antibodies and vaccine efforts, but the gH/UL116/UL141 trimer is predicted to escape such recognition.” This helps CMV establish latency and long-term infection without being detected by the immune system.
“Previous attempts to generate a CMV vaccine have failed, but that was before we identified the GATE complex,” noted Chris Benedict, PhD, associate professor at La Jolla Institute and co-senior author. “We hope that new strategies targeting GATE will improve our chances to combat CMV infection, and also perhaps cleanse our bodies of this lifelong infection.”
Implications beyond CMV
The findings suggest that other herpesviruses, including Epstein-Barr virus and varicella-zoster (chickenpox), may also use similar mechanisms to spread. This discovery opens the door to new avenues in vaccine and antiviral drug development not just for CMV but possibly across the herpesvirus family.
“If we can develop antiviral drugs or vaccines that inhibit CMV entry,” Benedict said, “this will allow us to combat the many diseases this virus causes in developing babies and immune-compromised people.”
