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TitleAntibody escape by polyomavirus capsid mutation facilitates neurovirulence.
Journal, issue, pagesElife, Vol. 9, Year 2020
Publish dateSep 17, 2020
AuthorsMatthew 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 /
PubMed AbstractJCPyV polyomavirus, a member of the human virome, causes progressive multifocal leukoencephalopathy (PML), an oft-fatal demyelinating brain disease in individuals receiving immunomodulatory therapies. ...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.
External linksElife / PubMed:32940605 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 4.2 Å
Structure data

22640

7k22

EMDB-22640, PDB-7k22:
Murine polyomavirus pentavalent capsomer with 8A7H5 Fab, subparticle reconstruction
Method: EM (single particle) / Resolution: 3.2 Å

22641

7k23

EMDB-22641, PDB-7k23:
Murine polyomavirus hexavalent capsomer with 8A7H5 Fab, subparticle reconstruction
Method: EM (single particle) / Resolution: 3.3 Å

22642

7k24

EMDB-22642, PDB-7k24:
Murine polyomavirus pentavalent capsomer, subparticle reconstruction
Method: EM (single particle) / Resolution: 2.9 Å

22643

7k25

EMDB-22643, PDB-7k25:
Murine polyomavirus hexavalent capsomer, subparticle reconstruction
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-22645:
Murine polyomavirus (icosahedral reconstruction)
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-22646:
Murine polyomavirus with 8A7H5 Fab (icosahedral reconstruction)
Method: EM (single particle) / Resolution: 4.2 Å

Source
  • rattus norvegicus (Norway rat)
  • Murine polyomavirus strain A2
  • mus musculus polyomavirus 1
KeywordsVIRAL PROTEIN / polyomavirus / capsomer / VP1 / Fab

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