JC polyomavirus mutants escape antibody-mediated neutralization

Abstract

JC polyomavirus (JCV) persistently infects the urinary tract of a majority of adults. Under conditions of immune impairment, JCV causes an opportunistic brain disease, progressive multifocal leukoencephalopathy (PML). JCV strains found in the cerebrospinal fluid (CSF) of PML patients contain distinctive mutations in surface loops of the major capsid protein, VP1. We hypothesized that VP1 mutations might allow the virus to evade antibody-mediated neutralization. Consistent with this hypothesis, neutralization serology revealed that plasma samples from PML patients neutralized wild-type JCV strains but failed to neutralize patient-cognate PML-mutant JCV strains. This contrasted with serological results for healthy individuals, most of whom robustly cross-neutralized all tested JCV variants. Mice administered a JCV virus-like particle (VLP) vaccine initially showed neutralizing “blind spots” (akin to those observed in PML patients) that closed after booster immunization. A PML patient administered an experimental JCV VLP vaccine likewise showed dramatically increased neutralizing titer against her cognate PML-mutant JCV. The results indicate that deficient humoral immunity is a common aspect of PML pathogenesis and that vaccination may overcome this humoral deficiency. Thus, vaccination with JCV VLPs might prevent the development of PML.

Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

“…Probably more importantly, intrathecal JCPyV-specific antibody titers strongly rise and are considered as diagnostic evidence of ongoing PML in patients with clinical findings compatible with PML and, at the same time, with low or absent JCPyV DNA in the CSF, which is usually the case when IRIS has begun (12, 17, 28). Finally, the rise in CSF JCPyV antibodies with specificity against several PML variants including the one found in the CSF in a patient after vaccination with JCPyV VP1/VLP (35) argues that a B cell/antibody response in the CNS compartment plays an active role in containing and/or eliminating the virus.…”

“…Support for this assumption stems from a patient with idiopathic CD4 lymphopenia, whom we successfully vaccinated with JCPyV VP1/virus-like particles (VLPs), imiquimod, and recombinant IL-7, as previously shown (14). In this patient, the JCPyV-specific antibody response rapidly increased after vaccination and broadened with respect to recognition of PML variants including the one infecting the patient, and in parallel to the increasing antibody response, the patient’s cerebrospinal fluid (CSF) JCPyV viral load declined to zero (35). …”

Virus Like Nanoparticles: Display Matters

“…In a recent study, VLP based vaccination strategy was tested in a PML (progressive multifocal leukoencephalopathy) patient who had idiopathic CD4 + T cell lymphocytopenia, a syndrome where CD4+ T lymphocyte count of the body is extremely low exhibiting a non-HIV (Human Immuno Deficiency Virus)-AIDS (Acquired Immuno Deficiency Syndrome)-like situation. PML is a fatal neurodegenerative brain disease caused by uncontrolled replication of JC polyomavirus (JCV) in brain of immuno-compromised individuals.The JCV VLP based vaccine could elicit humungous anti-JCV neutralizing antibody response with a parallel decline in viral load in blood and significant decrease in PML lesion size in brain (Ray et al, 2015). This clearly demonstrated the efficacy of VLPs, particularly because of the fact that this patient had CD4 + T cell lymphocytopenia.…”

“…Many viral surface antigens have the ability to selfassemble into VLPs that resemble the native viral particles in appearance, for example, in case of Human Papillomavirus (Kemp et al, 2011;Schiller and Muller, 2015), JC polyomavirus (Ray et al, 2015), BK polyomavirus (Pastrana et al, 2013) etc. Many others that cannot self-assemble, or those where the viral capsid is encased inside a lipid envelope, or those where the viral surface proteins are relatively mobile/ not rigid, can also potentially be displayed in a more rigid and thermodynamically stable fashion as synthetic VLPs.…”

Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

“…The high frequency of amino acid mutations in VP1 close to or at the receptor binding site in isolates of JCV from PML patients suggests that subtle changes in binding affinity for sialylated receptors can significantly affect viral pathogenicity (70). Recent evidence indicates that mutations in VP1 may serve to enable escape from neutralizing JCV antibodies (71,72). PML nonsurvivors had selectively impaired JCV-specific CD8 T cell responses (16,73).…”