A Common, Silent Virus May Be Behind Parkinson's Worsening

Researchers have discovered that a virus called human pegivirus appeared in half the brains of people with Parkinson's disease, but not in people without the disease. This virus appears to disrupt the immune system and cell function, which can accelerate brain damage. The results suggest that, in addition to genetics, viral infections may also influence the development and severity of Parkinson's.

Parkinson's disease is a progressive neurological condition that primarily affects movement, but can also affect other bodily functions. It has no single cause: both genetics and environmental factors contribute to its development. Among these environmental factors, viral infections have been investigated as possible triggers that may favor the onset or progression of the disease.

In this study, scientists at Northwestern University Feinberg School of Medicine, USA, decided to investigate whether viruses were present in the brains of people with Parkinson's. To do so, they used a technology called virome sequencing, which allows the identification of all the genetic material of viruses present in a sample, even those not expected to be found.

They also used a method called quantitative polymerase chain reaction, which serves to confirm and measure the presence of viruses very precisely. Human pegivirus (HPgV, formerly called GB-C virus) is quite different from most known viruses because it often causes no apparent symptoms.

Many people may have the virus in their blood without ever realizing it, as it is not linked to specific illnesses such as fever, pain, or inflammation typical of viral infections. In some studies, it has even been suggested that HPgV could have protective effects in certain conditions, such as HIV progression.

There is still no clear evidence that it causes symptoms on its own; when it appears in medical research, it is usually in association with other diseases or in the context of the immune system. In other words, human pegivirus, on its own, does not usually cause recognizable symptoms in infected people.

Human Pegivirus

The results showed that half of the brains of Parkinson's patients analyzed had a virus called human pegivirus. In the comparison group, made up of people without Parkinson's and of the same age and sex, none of the cases had this virus.

In some brains that tested positive for pegivirus, the scientists also used a technique that stains tissue and confirmed the presence of the virus within the nervous system.

But it wasn't just the presence of the virus that attracted attention. Parkinson's patients with pegivirus showed more intense changes in brain structure, typical of the progression of the disease, such as increased levels of certain proteins linked to communication between neurons.

When the virus was present in the blood, the scientists noted other changes, such as different levels of molecules associated with cell growth and the functioning of mitochondria, which are the cells' "powerhouses." This suggests that the virus may disrupt important cellular maintenance and cleansing processes, contributing to the worsening of the disease.

(A and B) Subcortical oligodendrocytes (black arrowheads) from 2 control individuals with no evidence of HPgV infection. (C) Nuclear immunoreactivity of human pegivirus (HPgV) in an oligodendrocyte (white arrow) in the subcortical white matter of a patient with Parkinson's disease (PD). (D) Cytoplasmic immunostaining of human pegivirus (white arrowhead) and nuclear immunoreactivity of human pegivirus in an oligodendrocyte (white arrow) in the subcortical white matter of another patient with Parkinson's disease.

Furthermore, a detailed analysis of the genetic material showed that the virus appeared to interfere with the activity of the immune system, particularly by reducing signals related to a molecule called interleukin-4, which normally participates in processes regulating the inflammatory response. This alteration was found in both the blood and the brain.

Scientists also analyzed blood samples over time and found that the response to the virus varied depending on the type of mutation patients had in a gene called LRRK2, already known to be linked to Parkinson's risk.

This showed that the interaction between the virus and the organism may depend on each person's genetic makeup. Another gene, called YWHAB, appeared central to this network of interactions, showing altered connections with important immune system genes in patients infected with the Pegivirus.

The YWHAB gene produces a protein that helps cells communicate and regulate important processes such as growth, survival, and stress response.

Taken together, the results suggest that human pegivirus may play an important role in the progression of Parkinson's disease, not as a sole cause, but as a factor that interferes with both immune system function and brain cellular maintenance processes. This highlights how Parkinson's disease may result from a complex interplay between viral infection, genetics, and brain vulnerability.

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Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson's disease

Barbara A Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S Orban, Bernabe Bustos, Steven J Lubbe, Rudolph J Castellani, and  Igor J Koralnik

JCI Insight . 2025 Jul 8; 10(13): e189988. 

doi: 10.1172/jci.insight.189988.

Abstract: 

Parkinson's disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype-dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.