HSV-1 Reprograms Brain Immune Cells in Alzheimer’s Research

Researchers at the University of Colorado Anschutz Medical Campus have found that herpes simplex virus type 1 (HSV-1), the virus responsible for common cold sores, can alter the brain’s resident immune cells and their gene activity. Published in PLOS Pathogens on October 1, 2026, the study identified changes in microglia that resemble immune patterns associated with Alzheimer’s disease, although the findings do not establish that HSV-1 causes the condition.

The findings show that HSV-1 infection pushes microglia toward an interferon-dominated antiviral response while reducing the activity of genes responsible for maintaining healthy brain tissue. According to the researchers, these changes affect the cells’ ability to support normal neural functions, including synaptic pruning and the removal of cellular waste.

The study also found that the virus changes chromatin accessibility, which influences how cells regulate gene expression. The research team combined single-nucleus RNA sequencing, chromatin accessibility profiling, and spatial proteomics and transcriptomics to investigate microglial responses in an intranasal HSV-1 infection model.

Christy Niemeyer, PhD, assistant professor of neurology at CU Anschutz and the study’s senior author, described the competing demands placed on these immune cells during infection.

“Microglia act as both the brain’s security system and its maintenance crew,” Niemeyer said. “When HSV-1 enters the brain, these cells shift into emergency defense mode. While this helps fight the virus, it may also compromise their ability to perform the everyday functions, even after the virus is gone.”

The researchers found that the changes were concentrated in specific brain microenvironments where the virus was present, rather than distributed uniformly throughout the brain. Their analysis also indicated that HSV-1 exposure reorganized chromatin, changing which sections of DNA remained accessible to the machinery responsible for gene transcription.

Niemeyer emphasized that the findings extend beyond a conventional inflammatory response.

“What makes these findings particularly interesting is that the virus isn’t simply triggering inflammation,” Niemeyer said. “It’s changing the molecular programs that control how these immune cells function. An important question is whether these changes persist after infection.”

The altered microglial profiles also resembled patterns observed in neurodegenerative disease and in response to factors associated with aging and genetic risk. Kimberley Bruce, PhD, associate professor of medicine at CU Anschutz and co-senior author, said the findings identify a shared biological feature without demonstrating a direct causal relationship between HSV-1 and Alzheimer’s disease.

Bruce explained the significance of the molecular similarities between infection-related immune changes and those observed in Alzheimer’s research.

“Interestingly, the way that HSV-1 finely tunes the immune response in microglia resembles patterns found in response to other factors that drive Alzheimer’s disease,” Bruce said. “Although we have not established that HSV-1 causes Alzheimer’s, it highlights the immune programming of microglia as a common factor linking infection, aging and genetic risk factors.”

Alzheimer’s disease is a complex condition influenced by multiple factors, including genetic predispositions such as the APOE4 allele and environmental exposures. The study provides a model for investigating whether repeated infections or periods of viral reactivation could influence microglial function over time, potentially affecting the brain’s ability to manage harmful protein accumulation.

Niemeyer said understanding how HSV-1 alters the brain’s immune environment could help explain differences in vulnerability to neurodegeneration.

“Understanding how a common virus changes the brain’s immune environment may help us identify why some individuals become more vulnerable to neurodegeneration,” Niemeyer said.

The research team is preparing follow-up studies to determine whether HSV-1-related chromatin changes become permanent and how intermittent viral reactivation over decades may affect long-term cognitive resilience.