In a discovery that challenges conventional understanding of viral behavior, University of Virginia researchers have identified how the herpes virus cunningly manipulates our own immune defenses to trigger those unwelcome cold sores.
The finding, published in the Proceedings of the National Academy of Sciences, reveals that herpes simplex virus 1 (HSV-1) deploys a surprising strategy when reactivating from dormancy—it deliberately provokes the body’s immune response as part of its escape plan.
“Our findings identify the first viral protein required for herpes simplex virus to wake up from dormancy, and, surprisingly, this protein does so by triggering responses that should act against the virus,” said Dr. Anna Cliffe from UVA’s Department of Microbiology, Immunology and Cancer Biology, who led the research.
This counterintuitive approach—where the virus intentionally alerts the immune system—represents a significant shift in how scientists understand herpes reactivation. Rather than staying hidden to avoid detection, the virus appears to deliberately set off alarm bells.
A Viral Sixth Sense
The research team discovered that HSV-1 makes a protein called UL12.5 to reawaken itself from dormancy. While we’ve long known that stress, sunburns, and other infections can trigger cold sores, this protein provides a previously unknown internal mechanism for viral reactivation.
“We were surprised to find that HSV-1 doesn’t just passively wait for the right conditions to reactivate—it actively senses danger and takes control of the process,” explained researcher Patryk Krakowiak, a co-author of the study. “Our findings suggest that the virus may be using immune signals as a way to detect cellular stress—whether from neuron damage, infections or other threats—as a cue to escape its host and find a new one.”
The discovery has significant implications considering that HSV-1 infects more than 60% of people under 50 worldwide—approximately 3.8 billion individuals, according to World Health Organization estimates.
Beyond Just Cold Sores
While many associate HSV-1 primarily with those annoying lip blisters, its impact extends much further. The virus can cause genital herpes (now with more new U.S. cases attributed to HSV-1 than to HSV-2), viral encephalitis (brain inflammation), and has been linked to Alzheimer’s disease development.
The Virginia researchers also discovered that herpes simplex virus 2, which traditionally causes most genital herpes cases, produces the same protein and likely uses a similar reactivation mechanism. This suggests the finding could lead to treatments for both oral and genital herpes.
Perhaps most intriguing was the team’s observation that the UL12.5 protein wasn’t necessary for viral reactivation when another infection was present. The scientists believe this occurs because other infections trigger certain “sensing pathways”—essentially the neuronal equivalent of a home security system—that the herpes virus can detect and exploit.
A Persistent Problem
Once HSV-1 infects someone, it remains in their body permanently. The immune system can force it into a dormant state, allowing people to remain symptom-free for extended periods. However, this new research reveals that the virus isn’t simply waiting passively during dormancy—it’s actively monitoring its environment for opportunities to reemerge.
The virus appears capable of hijacking the very same immune responses designed to protect us, turning our defenses into signals for its reactivation. This helps explain why so many different triggers—from emotional stress to sunburn—can cause cold sore flare-ups in different individuals.
Toward Better Treatments
While current antiviral medications can help manage outbreaks, no existing therapies can prevent the virus from reactivating in the first place. The UVA discovery potentially changes this outlook.
“Currently, there are no therapies that can prevent the virus from waking up from dormancy, and this stage was thought to only use host proteins,” Cliffe noted. “Developing therapies that specifically act on a viral protein is an attractive approach that will likely have fewer side effects than targeting a host protein.”
The research team is already pursuing this promising avenue.
“We are now following up on this work to investigate how the virus is hijacking this response and testing inhibitors of UL12.5 function,” said Cliffe.
The study represents a meaningful step toward preventative treatments that could stop cold sores before they start. For billions of people worldwide who experience the discomfort and social awkwardness of herpes outbreaks, such a development would be a welcome relief—and one that comes from understanding the surprisingly crafty ways this ancient virus has evolved to outsmart our defenses.
The research was funded by various grants from the National Institute of Health, the Owens Family Foundation, a UVA Global Infectious Disease Institute seed award, and UVA Wagner Fellowships.