Antibody escape by polyomavirus capsid mutation facilitates neurovirulence

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.

T Cell Deficiency Precipitates Antibody Evasion and Emergence of Neurovirulent Polyomavirus

“…Although depressed anti-JCPyV T cell immunity is the dominant risk factor for PML, JCPyVs in the CNS of PML patients have VP1 mutations that allow evasion of antiviral (Cortese et al, 2021;Jelcic et al, 2015;Lauver et al, 2020;Pavlovic et al, 2018;Ray et al, 2015). To connect T cell deficiency and VP1-specific Ab-escape JCPyV variants, we investigated T cell insufficiency in mice infected by MuPyV in the setting of a restricted VP1 antibody response.…”

High-resolution asymmetric structure of a Fab–virus complex reveals overlap with the receptor binding site

“…For Fab E (Bottom), a severe deficit of the most proximal RDF component was observed, consistent with twofold symmetry clash of Fab E. Example geometry corresponding to RDF components are shown in each case. (44,46). The subparticle was defined by docking a crystal structure of Fab 14 (PDB ID: 3GK8) into the density map (18) and extracted using icosahedral subparticle extraction and correlated classification (ISECC) (47).…”

“…Subparticle classification was done with localized reconstruction scripts and 3D classification in RELION ( 44 , 46 ). The subparticle was defined by docking a crystal structure of Fab 14 (PDB ID: 3GK8) into the density map ( 18 ) and extracted using icosahedral subparticle extraction and correlated classification (ISECC) ( 47 ).…”

Mechanisms of viral persistence in the brain and therapeutic approaches

“…For example, JC virus that persists in the CNS has been shown to have mutations in the capsid protein VP1. These mutations result in decreases in CD4+ T-cell and effector cell responses against the virus [76] as well as rendering the virus resistant to neutralizing antibodies [77]. Importantly, these mutations are also associated with enhanced neurovirulence.…”