1. Immunology and Inflammation
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Antibody escape by polyomavirus capsid mutation facilitates neurovirulence

  1. Matthew D Lauver
  2. Daniel J Goetschius
  3. Colleen S Netherby-Winslow
  4. Katelyn N Ayers
  5. Ge Jin
  6. Daniel G Haas
  7. Elizabeth L Frost
  8. Sung Hyun Cho
  9. Carol Bator
  10. Stephanie M Bywaters
  11. Neil D Christensen
  12. Susan L Hafenstein
  13. Aron E Lukacher  Is a corresponding author
  1. Penn State College of Medicine, United States
  2. The Pennsylvania State University, United States
  3. University of Virginia, United States
  4. Huck Institutes of the Life Sciences, United States
Research Article
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Cite this article as: eLife 2020;9:e61056 doi: 10.7554/eLife.61056

Abstract

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.

Data availability

All maps and models are deposited at wwPDB and their accession numbers are provided in the Data and code availability section of our manuscript.Maps and coordinates (4 zip files) generated during this study are included in the manuscript and supporting files.Source data files have been provided for Figures 4 and 5 and for Supplemental Figure 4, and are available on GitHub with the URL provided in the Data and code availability section.

The following data sets were generated

Article and author information

Author details

  1. Matthew D Lauver

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel J Goetschius

    Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6052-7141
  3. Colleen S Netherby-Winslow

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katelyn N Ayers

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ge Jin

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniel G Haas

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Elizabeth L Frost

    Neuroscience, University of Virginia, Charlottesville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sung Hyun Cho

    Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Carol Bator

    Biochemistry and Molecular Biology, Huck Institutes of the Life Sciences, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Stephanie M Bywaters

    Pathology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Neil D Christensen

    Pathology, Penn State College of Medicine, Hershey, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Susan L Hafenstein

    Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Aron E Lukacher

    Microbiology and Immunology, Penn State College of Medicine, Hershey, United States
    For correspondence
    alukacher@pennstatehealth.psu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7969-2841

Funding

National Institute of Neurological Disorders and Stroke (R01NS088367)

  • Aron E Lukacher

National Institute of Neurological Disorders and Stroke (R01NS092662)

  • Aron E Lukacher

National Institute of Allergy and Infectious Diseases (R01AI107121)

  • Susan L Hafenstein

National Institute of Neurological Disorders and Stroke (F32NS106730)

  • Colleen S Netherby-Winslow

National Institute of Neurological Disorders and Stroke (F31NS083336)

  • Elizabeth L Frost

National Cancer Institute (T32CA060395)

  • Matthew D Lauver

National Cancer Institute (T32CA60395)

  • Stephanie M Bywaters

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments involving mice were conducted with the approval of Institutional Animal Care and Use Committee (Protocol 47619) of The Pennsylvania State University College of Medicine in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The Pennsylvania State University College of Medicine Animal Resource Program is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC). The Pennsylvania State University College of Medicine has an Animal Welfare Assurance on file with the National Institutes of Health's Office of Laboratory Animal Welfare; the Assurance Number is A3045-01.

Reviewing Editor

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: July 14, 2020
  2. Accepted: September 17, 2020
  3. Accepted Manuscript published: September 17, 2020 (version 1)
  4. Version of Record published: October 7, 2020 (version 2)
  5. Version of Record updated: October 9, 2020 (version 3)

Copyright

© 2020, Lauver et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    The alpha/B.1.1.7 SARS-CoV-2 lineage emerged in autumn 2020 in the United Kingdom and transmitted rapidly until winter 2021 when it was responsible for most new COVID-19 cases in many European countries. The incidence domination was likely due to a fitness advantage that could be driven by the receptor-binding domain (RBD) residue change (N501Y), which also emerged independently in other variants of concern such as the beta/B.1.351 and gamma/P.1 strains. Here, we present a functional characterization of the alpha/B.1.1.7 variant and show an eightfold affinity increase towards human angiotensin-converting enzyme-2 (ACE-2). In accordance with this, transgenic hACE2 mice showed a faster disease progression and severity after infection with a low dose of B.1.1.7, compared to an early 2020 SARS-CoV-2 isolate. When challenged with sera from convalescent individuals or anti-RBD monoclonal antibodies, the N501Y variant showed a minor, but significant elevated evasion potential of ACE-2/RBD antibody neutralization. The data suggest that the single asparagine to tyrosine substitution remarkable rise in affinity may be responsible for the higher transmission rate and severity of the B.1.1.7 variant.

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    T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes – groups of biochemically similar TCRs – that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.