EMD-22641
Murine polyomavirus hexavalent capsomer with 8A7H5 Fab, subparticle reconstruction
EMD-22641
Single-particle3.3 Å
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Map released: 07/10/2020
Last modified: 23/10/2024
Sample Organism:
Rattus norvegicus,
Murine polyomavirus strain A2,
Mus musculus polyomavirus 1
Sample: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
Fitted models: 7k23 (Avg. Q-score: 0.512)
Deposition Authors: Goetschius DJ
,
Hafenstein SL
Sample: 8A7H5 Fab light chain, 8A7H5 Fab heavy chain, Capsid protein VP1
Fitted models: 7k23 (Avg. Q-score: 0.512)
Deposition Authors: Goetschius DJ
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Antibody escape by polyomavirus capsid mutation facilitates neurovirulence.
Lauver MD
,
Goetschius DJ
,
Netherby-Winslow CS,
Ayers KN
,
Jin G,
Haas DG,
Frost EL,
Cho SH,
Bator C,
Bywaters SM,
Christensen ND,
Hafenstein SL,
Lukacher AE
(2020) eLife , 9
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(2020) eLife , 9
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.
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.