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Human pegivirus (HPgV) — a member of the flavivirus family and long considered harmless — has emerged as a potential environmental trigger or contributor to Parkinson’s disease (PD).

Researchers found the virus in brain tissue and cerebrospinal fluid from half the samples from people with PD but in none of those from people without the condition. Although investigators found other viruses in brain tissue, they were present in those with and without PD.

“HPgV was the only virus we found to be unique in PD patients as compared to controls in the brain,” first author Barbara Hanson, PhD, Department of Neurology and Pathology, Feinberg School of Medicine, Northwestern University, Chicago, told Medscape Medical News.

“We think it’s too early to draw any conclusions on what role HPgV might play in Parkinson’s disease, but we definitely feel that more work needs to be done to determine whether that is a possibility,” Hanson added.

The study was published online recently in JCI Insight.

Surprising Finding

Investigators analyzed postmortem brain samples from 10 patients with PD and 14 age- and sex-matched unaffected control individuals using an assay the team developed called ViroFind, which allows for the detection of every virus known to infect humans in clinical biosamples.

They found HPgV in the postmortem brains of half of the brains from people with PD and in none of the brains in the control group. HPgV, a blood-borne virus, is in the same family as hepatitis C but is not known to cause disease.

“A number of other viruses were also found in brain tissue, but they were all identified in both PD and control brains, they were also typical components of the brain virome from other studies as well,” Hanson explained.

“HPgV is a common, symptomless infection previously not known to frequently infect the brain. We were surprised to find it in the brains of Parkinson’s patients at such high frequency and not in the controls,” corresponding author Igor Koralnik, MD, chief of Neuroinfectious Diseases and Global Neurology, Northwestern University, said in a statement.

The presence of HPgV also tracked with neuropathology. Patients with PD who had HPgV detected in brain tissue exhibited more advanced or distinct neuropathologic changes, including increased tau pathology and altered levels of certain brain proteins. In addition, complexin-2 levels — a marker of excitatory neurotransmission — were elevated in the presence of HPgV.

HPgV infection was also associated with altered immune signaling, including consistent suppression of interleukin-4 (IL-4) signaling, as well as altered gene expression profiles in both the central nervous system and blood.

A Closer Look

Longitudinal analysis of blood samples from more than 1000 participants in the Parkinson’s Progression Markers Initiative showed a genotype-dependent viral response.

In patients with the PD-related gene mutation — LRRK2 — the signals from the immune system were different in response to the virus compared with patients with PD without the mutation.

Finding that the immune system responded differently to HPgV, depending on a person’s genetics, was unexpected.

“This suggests it could be an environmental factor that interacts with the body in ways we didn’t realize before,” Koralnik said.

“We plan to look more closely at how genes like LRRK2 affect the body’s response to other viral infections to figure out if this is a special effect of HPgV or a broader response to viruses,” Koralnik added.

Gene-Environment-Immune Triad

Reached for comment, Shaheen Lakhan, MD, neurologist and researcher based in Miami, said this study caught his attention “not just for identifying pegivirus in the brains of people with Parkinson’s disease, which is novel on its own, but because it gestures toward a deeper insight: the convergence of genes, environment, and immunity in neurodegeneration, or what I call the ‘gene-environment-immune triad’,” he said.

“Rather than a singular trigger, it suggests that disease emerges from the interplay between a person’s genetic risk, latent or subclinical infections, and the way their immune system responds,” said Lakhan, who wasn’t involved in the study.

“Pegivirus has long been considered harmless. Finding it active in the brain and cerebrospinal fluid of Parkinson’s patients, but not in controls, and seeing immune signatures that change based on LRRK2 genotype, raises the possibility that this virus is not just a passenger. It might be a modifier, or even a catalyst, in a vulnerable host,” Lakhan said.

He noted that this gene-environment-immune triad pattern has been seen before, including Epstein-Barr virus in multiple sclerosis and herpes simplex virus 1 in Alzheimer’s disease. Even type 1 diabetes follows this script, where enteroviruses like coxsackievirus B may initiate beta-cell autoimmunity only in those with certain human leukocyte antigen class II haplotypes, Lakhan said.

He noted that these are not simple “cause-and-effect stories. They are stories of interaction, between host and virus, gene and environment, immunity and identity.”

What makes the pegivirus study different is its depth, Lakhan said.

“The researchers don’t just detect viral RNA. They show that immune signaling pathways, especially IL-4, respond differently to pegivirus depending on LRRK2 mutation status. This is not just about whether a virus is present, but how the body reacts to it, and how that reaction depends on inherited risk,” he said.

In his view, pegivirus might not initiate PD, but could serve as a “second hit that worsens pathology or tips the balance in those already on the edge,” he said.

“That might explain why some carriers of LRRK2 mutations never develop disease, while others do, depending on what viruses they carry or how their immune systems handle them,” Lakhan added.

The idea that viruses may influence the nervous system, health, and disease isn’t new, Lakhan said. But this study shows how the immune response intersects with the genetic background to bring about that influence, he added.

“If this line of research continues, we may need to fundamentally rethink how we define causality in neurodegenerative diseases,” he said. “It’s not about one agent acting in isolation. It’s about the dialogue between genes, viruses, and immune networks. Pegivirus may have just given us a glimpse of how that conversation turns into disease.”

This research was supported by grants from the Michael J. Fox Foundation and the National Institute on Aging. Hanson, Koralnik, and Lakhan had no relevant disclosures.