Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

Abstract

OBJECTIVE: Symptomatic infections of the central nervous system (CNS) with JC polyomavirus (JCV) usually occur as a result of immunocompromise and manifest as progressive multifocal leukoencephalopathy (PML) or granule cell neuronopathy (GCN). After immune reconstitution, some of these cases may show long-term persistence of JCV and delayed clinical improvement despite inflammation. METHODS: We followed 4 patients with multiple sclerosis, who developed natalizumab-associated PML or GCN with regard to JC viral load and JCV-specific T-cell responses in the CNS. All of them experienced immune reconstitution inflammatory syndrome (IRIS), but in 2 cases JCV persisted > 21 months after IRIS accompanied by delayed clinical improvement. RESULTS: Persistence of JCV was associated with a lack of JCV VP1-specific T-cell responses during immune reconstitution in 1 of the patients. Detailed analysis of the brain infiltrate in another patient with neuronal persistence of JCV revealed strong infiltration of CD8(+) T cells and clonal expansion of activated CD8(+) effector T cells with a CD4(dim) CD8(+) phenotype, both exhibiting exquisite specificity for conserved epitopes of JCV large T antigen. However, clearance of JCV was not efficient, because mutations in the major capsid protein VP1 caused reduced CD4 ( -3-

Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned

“…Other VP1 variants have been reported that may have escaped immune control with mutations in the VP1 sequences that were identified in the CSF of PML patients with specific T cell responses so attributed as the potential PML causative variant. 40 However, almost all PML patients with ELISA demonstrated antibody to JCV have the prototype variant in brain and CSF.…”

“…This observation had led to the hypothesis of VP-1 gene rearrangement that could result in a more 'neurovirulent' variant leading to PML. 39,40 This observation warrants further investigation that would require 'deep sequencing' studies. 41 However, it appears that PML patients are infected with the prototype VP-1 protein since that is the antigen used in the ELISA assays of commercial, academic and government laboratories.…”

“…It is possible that immune escape of JCV VP-1 variants could occur due to either persistent JCV in cell compartments or mutations in the VP-1 gene to avoid immune recognition. 40 This has been an area of new investigation in the last several years.…”

Current multiple sclerosis treatments have improved our understanding of MS autoimmune pathogenesis

“…Risk stratification with anti JC polyoma virus antibody titers has helped in determining in which patients the treatment is relatively safe, but, despite the high efficacy and overall very good tolerability, the risk of PML is a serious problem when treating MS patients with NTZ. Ongoing research tries to identify why NTZ, which targets a very specific cell–cell interaction, contributes to such a rare viral infection .…”

Lack of specific T- and B-cell clonal expansions in multiple sclerosis patients with progressive multifocal leukoencephalopathy

“…A limitation of this study is that the analysis was limited to peripheral blood, while analysis of lymphocytes present in CSF or in the brain may provide more valuable information for a better understanding of natalizumab-associated PML 7,42 . Indeed, it has been reported that in these patients the CSF T-cell pool is not only diminished quantitatively, but it is also characterized by a reduced TR heterogeneity 13,[49][50][51] .…”