Summary: Genetic mutations in the capsid of JCPyV can enable the virus to evade neutralizing antibodies, increasing the risk of brain infection.
Source: Penn State
Researchers at Penn State College of Medicine report that a single genetic change in the outer shell of a polyomavirus can allow the virus to escape antibody recognition. Their findings indicate that screening for such mutations in patients receiving immunosuppressive or immune-modulating therapies could help identify those at greater risk of developing progressive multifocal leukoencephalopathy (PML), a severe and often fatal brain disease.
Investigators led by Dr. Aron Lukacher, professor and chair of the Department of Microbiology and Immunology, and Susan Hafenstein, professor of medicine and microbiology and immunology and professor of biochemistry and molecular biology, examined the structural and functional consequences of a capsid mutation using mouse polyomavirus (MuPyV) as a model. MuPyV serves as a genetic and biologic proxy for JC polyomavirus (JCPyV), the human virus that normally persists harmlessly in many people but can cause PML in individuals whose immune systems are weakened by disease or treatment.
Mutations in the major capsid protein VP1 of JCPyV are commonly found in samples from patients with PML, yet it has been unclear whether these changes directly increase the virus’s ability to infect the brain or instead allow the virus to escape neutralizing antibodies and thereby gain access to neural tissues. To address this question, the Penn State team introduced a VP1 mutation in MuPyV that mirrors a frequent JCPyV alteration observed in PML patients.
This mutation substitutes a single amino acid in the viral capsid, altering the surface features that antibodies typically recognize. In controlled experiments the mutated MuPyV replicated poorly in the kidney—an important reservoir for polyomavirus persistence—while maintaining its capacity to infect the central nervous system and cause neuropathology, including hydrocephalus (brain swelling). These results suggest that the mutation shifts the virus’s tissue distribution and pathogenic potential without abolishing its neurotropism.
To investigate how the mutation affects antibody binding, the researchers used cryogenic electron microscopy (cryo-EM) to obtain high-resolution, three-dimensional structures of virus particles in complex with monoclonal antibodies. Team members included doctoral student Matthew Lauver and medical scientist training program student Daniel Goetschius. Their structural analyses, reported in the journal eLife, reveal that the mutation disrupts the antibody’s ability to engage the capsid surface, thereby preventing neutralization.
Structural mapping showed that the antibody’s binding footprint overlaps with regions altered by the VP1 mutation. By changing a key residue on the capsid surface, the virus reduces or eliminates critical contacts with the monoclonal antibody, creating what investigators describe as antibody escape. Importantly, the monoclonal antibody studied shares specificity with components of the natural anti-VP1 immune response, indicating that similar escape mechanisms could operate in infected humans.
Lukacher noted that while many VP1 mutations reduce viral replication in the kidney, only a subset confer the ability to resist neutralizing antibodies. This distinction matters clinically: mutations that both retain neurovirulence and promote antibody evasion pose the greatest danger for immunosuppressed patients because they can persist undetected and later invade the brain.
The research team emphasizes the need for further work to catalog which specific JCPyV mutations drive antibody escape in humans and to determine how often such variants arise in patients under different forms of immune suppression. Ultimately, they envision developing molecular screens to monitor patients with multiple sclerosis receiving immune-modulating drugs, as well as individuals with compromised immunity due to cancer or HIV/AIDS, so clinicians can identify and manage those at higher risk of PML.
About this neurology and genetics research news
Source: Penn State
Contact: Press Office – Penn State
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Original Research: Open access.
“Antibody escape by polyomavirus capsid mutation facilitates neurovirulence” by Matthew D. Lauver, Daniel J. Goetschius, Colleen S. Netherby-Winslow, Katelyn N. Ayers, Ge Jin, Daniel G. Haas, Elizabeth L. Frost, Sung Hyun Cho, Carol M. Bator, Stephanie M. Bywaters, Neil D. Christensen, Susan L. Hafenstein, Aron E. Lukacher. Published in eLife.
Abstract
Antibody escape by polyomavirus capsid mutation facilitates neurovirulence
JCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. Mutations in the major viral capsid protein, VP1, are common in JCPyV from PML patients (JCPyV-PML) but whether they confer neurovirulence or escape from virus-neutralizing antibody (nAb) in vivo is unknown. A mouse polyomavirus (MuPyV) with a sequence-equivalent JCPyV-PML VP1 mutation replicated poorly in the kidney, a major reservoir for JCPyV persistence, but retained the CNS infectivity, cell tropism, and neuropathology of the parental virus. This mutation rendered MuPyV resistant to a monoclonal Ab (mAb), whose specificity overlapped the endogenous anti-VP1 response. Using cryo-EM and a custom sub-particle refinement approach, we resolved an MuPyV:Fab complex map to 3.2 Å resolution. The structure revealed the mechanism of mAb evasion. Our findings demonstrate convergence between nAb evasion and CNS neurovirulence in vivo by a frequent JCPyV-PML VP1 mutation.