Researchers at the University of Pittsburgh School of Medicine and La Jolla Institute for Immunology have discovered a stealthy pathway that cytomegalovirus (CMV) uses to infiltrate blood vessels while evading immune response. This virus is the leading cause of birth defects in the United States. The virus creates a molecular “backdoor” by forming a hidden protein complex and bypassing the immune system. This discovery explains why vaccination attempts have failed for decades and opens up new avenues of targeted therapies that can prevent CMV-linked birth defects.
Researchers have previously discovered a mechanism by which CMV, a herpes virus, infects the majority of the world’s adult population by entering cells that line the blood vessels, thereby causing vascular disease. The virus uses molecular machinery shared by all herpes viruses. In addition to this mechanism, CMV employs another molecular “key” that allows the virus to sneak through by evading the body’s immune system.
The findings explain why prophylactic measures have failed against CMV. The research also opens up new routes for developing antiviral drugs in the future. This research can also inform new findings on how various herpes viruses utilize similar molecular structures to spread from one infected cell to another.
In the US, approximately one in every 200 babies is born with congenital CMV infection, with one in five having birth defects such as hearing loss or long-term health issues. CMV infections in adults are asymptomatic, but can be deadly for immunosuppressed individuals. CMV infection during pregnancy presents severe health risks to unborn children.
Due to the large size of CMV’s genome and complex molecular machinery, this virus escapes prophylactic treatments. Similar to other herpes viruses, CMV depends on a protein called gH to enter cells of the vessel lining. Other herpes viruses use a protein partner called gL to facilitate infection. However, according to this new study, CMV utilizes a different partner protein, called UL116, and recruits another protein, called UL141. The resulting protein complex of gH-UL116-UL141, referred to as GATE by the authors, then becomes an alternative tool for breaking into cells lining the blood vessels. This causes internal damage and prevents the immune system from recognizing the signs of infection. The newly discovered GATE could become a new target for potential vaccination efforts against CMV and other herpes viruses.
“Previous attempts to generate a CMV vaccine have failed, but that was before we identified the GATE complex. 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,” said Chris Benedict, Ph.D., associate professor at La Jolla Institute for Immunology and co-senior author of the study with Kamil and LJI professor, president & CEO Erica Ollmann Saphire, Ph.D., MBA. “If we can develop antiviral drugs or vaccines that inhibit CMV entry, this will allow us to combat the many diseases this virus causes in developing babies and immune-compromised people.”
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