Scientists discovered a new way to prevent cold sores

Scientists have uncovered a surprising strategy used by the herpes simplex virus (HSV-1) to reawaken in the body. A new study from the University of Virginia School of Medicine has identified a viral protein, UL12.5, that plays a key role in triggering viral reactivation.

The discovery challenges conventional understanding of how the virus escapes dormancy and could lead to new treatments for both cold sores and genital herpes.

HSV-1 is a highly contagious virus that infects over 60% of people under 50 worldwide, according to the World Health Organization. Once inside the body, the virus establishes a lifelong presence, lying dormant in nerve cells until reactivated by stress, illness, or even sun exposure.

While typically associated with cold sores, HSV-1 can also cause genital herpes, encephalitis, and has been linked to neurodegenerative diseases such as Alzheimer’s.

When HSV-1 infects a cell, the immune system detects its presence through pattern recognition receptors (PRRs), which sense viral components. These receptors activate pathways designed to eliminate the infection. However, viruses have evolved mechanisms to evade or manipulate these defenses.

A particularly surprising discovery is that HSV-1 does not merely wait for favorable conditions to reactivate—it actively participates in its own reawakening by triggering an immune response.

Researchers at UVA, led by Anna Cliffe, Ph.D., found that HSV-1 expresses the protein UL12.5, which stimulates the immune system in a way that paradoxically aids viral reactivation.

UL12.5 targets mitochondria, the cell’s energy-producing structures, causing them to release mitochondrial DNA (mtDNA) into the cytosol. This triggers the cGAS-STING pathway, a major immune response mechanism that typically fights infections.

Under normal circumstances, cGAS detects foreign DNA in the cytosol and activates STING, which initiates the production of interferons and other antiviral molecules.

However, HSV-1 exploits this pathway to reawaken from dormancy. By inducing mitochondrial stress and the release of mtDNA, UL12.5 sets off a chain reaction that promotes viral gene expression and 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,” said researcher Patryk Krakowiak. “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.”

Understanding how HSV-1 manipulates the immune system opens the door to new therapeutic strategies. Current antiviral drugs, such as acyclovir, only suppress viral replication during active infection but cannot prevent reactivation. The discovery of UL12.5’s role in awakening the virus suggests that targeting this protein could prevent outbreaks.

“We are now following up on this work to investigate how the virus is hijacking this response and testing inhibitors of UL12.5 function,” Cliffe said. “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.”

The study also found that in cases where another infection was present, HSV-1 did not require UL12.5 for reactivation. Instead, the immune response triggered by the second infection was sufficient to wake up the virus. This suggests that HSV-1 can use multiple pathways to reactivate, further complicating treatment strategies.

Beyond cold sores and genital herpes, HSV-1 has been linked to serious neurological conditions. Some research suggests that chronic inflammation from repeated HSV-1 reactivation may contribute to diseases such as Alzheimer’s. The ability of HSV-1 to manipulate immune pathways in neurons raises concerns about its long-term effects on brain health.

The virus establishes latency in neurons, where it remains dormant until certain conditions trigger reactivation. The absence of viral proteins during latency means that HSV-1 relies on host signaling pathways to initiate reactivation. One such pathway involves interleukin-1β (IL-1β), a key inflammatory cytokine. Previous studies have shown that IL-1β can induce HSV-1 reactivation by increasing neuronal excitability.

“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,” Cliffe explained. “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.”

With these new insights, scientists hope to develop treatments that prevent HSV-1 reactivation at its earliest stage. Inhibiting UL12.5 or blocking mitochondrial DNA release could be a strategy for reducing outbreaks and preventing the long-term inflammatory effects associated with recurrent infections.

The research has been published in the Proceedings of the National Academy of Sciences (PNAS), marking a significant step forward in understanding how herpes viruses manipulate the immune system.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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