In a groundbreaking study, researchers at the University of Virginia School of Medicine have made a significant discovery regarding the reactivation of the herpes simplex virus (HSV) in the body, offering hope for the development of targeted treatments for cold sores and genital herpes. Led by Anna Cliffe, Ph.D., and her team, the research uncovers an unexpected way the virus awakens from dormancy, with potential implications for managing not only cold sores but also genital herpes caused by the same virus.
The Surprising Role of the Virus in Reawakening
The findings, published in the Proceedings of the National Academy of Sciences, challenge the traditional understanding of how the herpes simplex virus reactivates. The virus, which has the ability to remain dormant in the body for long periods, was previously thought to only reawaken due to certain triggers like stress, illness, or sunlight. However, Cliffe’s team discovered that the herpes virus produces a protein, UL12.5, during its dormancy phase, which is involved in its escape from latency.
At first glance, triggering the body’s immune response might seem like a harmful move for the virus, almost akin to provoking an attack. After all, the immune system’s primary role is to detect and eliminate foreign invaders. But in a surprising twist, the virus appears to hijack the immune response to its advantage, using it as a means to escape from dormancy. This discovery opens up new avenues for research into how to stop the virus from reactivating and causing recurring outbreaks.
“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 Cliffe from the Department of Microbiology, Immunology, and Cancer Biology at UVA. “This is important because it gives us new ways to potentially prevent the virus from waking up and activating immune responses in the nervous system that could have negative consequences in the long term.”
The Role of Herpes Simplex Virus and its Impact
Herpes simplex virus 1 (HSV-1) is responsible for causing cold sores, one of the most common viral infections worldwide. According to the World Health Organization (WHO), more than 60% of people under 50 years old have been infected with HSV-1, which equates to over 3.8 billion people globally. In addition to cold sores, HSV-1 is now increasingly associated with genital herpes, a condition traditionally linked to another variant of the herpes virus, HSV-2.
The UVA researchers found that HSV-2, which was once thought to follow a different reactivation pathway, also produces the UL12.5 protein and may use a similar mechanism to reactivate. This discovery suggests that the same approach to preventing reactivation could potentially work for both HSV-1 and HSV-2, offering hope for a unified treatment for both cold sores and genital herpes.
Beyond these conditions, HSV-1 is also linked to more severe diseases, such as viral encephalitis (brain inflammation), and research suggests a potential connection to the development of Alzheimer’s disease.
Understanding the Mechanism of Virus Reactivation
One of the key insights from this study is how HSV-1 can sense when it’s in danger, triggering its reactivation process. The virus doesn’t just passively wait for the right conditions to reactivate—it actively senses external threats, such as neuron damage, infections, or cellular stress. Researchers believe that when the body experiences stress or an infection, the herpes virus detects these signals and begins to replicate, using these stress signals as a cue to escape its dormant state.
“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,” said Patryk Krakowiak, one of the lead researchers. “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.”
This discovery reveals that herpes not only takes advantage of the body’s natural immune system but actively manipulates it to ensure its survival. The protein UL12.5, which is produced by the virus during its dormant phase, plays a crucial role in this process by triggering responses that would normally work against the virus. By exploiting these immune responses, the virus ensures it remains able to replicate and spread, causing recurrent outbreaks.
Potential for New Treatments
Currently, there are no treatments that can prevent the herpes virus from reactivating once it has entered dormancy. Existing antiviral drugs can help reduce the severity and duration of outbreaks, but they do not address the root cause of reactivation. The findings from Cliffe’s team offer a promising new approach: targeting the UL12.5 protein directly to prevent the virus from reawakening.
“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. “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. 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.”
This could represent a significant breakthrough in the development of herpes treatments. Rather than targeting the body’s immune response, which can have side effects, new therapies could focus on inhibiting the viral protein, UL12.5, preventing the virus from exploiting the immune system to trigger reactivation.
Implications for Genital Herpes and Broader Virus Control
In addition to offering hope for better treatments for cold sores, this research also has important implications for the treatment of genital herpes, a condition that affects millions of people worldwide. HSV-1, once primarily responsible for oral herpes, is now increasingly recognized as a cause of genital herpes, with recent studies showing that new cases of genital herpes in the United States are more often caused by HSV-1 than HSV-2. Since HSV-2 also utilizes the UL12.5 protein to reactivate, the findings from this study suggest that the same therapeutic approach could be used to prevent reactivation in both oral and genital forms of herpes.
The ability to target viral proteins like UL12.5 could also have broader applications in controlling other types of viral infections. By understanding how viruses exploit the body’s natural immune mechanisms, scientists can develop more effective antiviral treatments that target the virus directly, rather than relying solely on the body’s immune response.
Conclusion
The discovery made by Anna Cliffe and her team at the University of Virginia represents a significant step forward in understanding how the herpes simplex virus reactivates from dormancy. The identification of the UL12.5 protein as a key factor in the virus’s reawakening provides new opportunities for developing targeted treatments for cold sores, genital herpes, and potentially other viral diseases caused by HSV. This research not only offers hope for better therapies but also contributes to our broader understanding of how viruses interact with the body’s immune system. As scientists continue to investigate the virus’s behavior and explore potential inhibitors of UL12.5, the future of herpes treatment looks promising, with the possibility of more effective, less invasive, and fewer side-effect therapies on the horizon.
Reference: Patryk A. Krakowiak et al, Co-option of mitochondrial nucleic acid–sensing pathways by HSV-1 UL12.5 for reactivation from latent infection, Proceedings of the National Academy of Sciences (2025). DOI: 10.1073/pnas.2413965122