Progressive Multifocal Leukoencephalopathy (PML) Development Is Associated With Mutations in JC Virus Capsid Protein VP1 That Change Its Receptor Specificity

Abstract

Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset. Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase. JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

“…Further studies will be needed to verify whether these findings can be confirmed when a transmigration model through brain microvascular endothelial cells is employed. Considering that the JC virus enters the CNS in a non-mutant form and capsid protein VP1 mutations can originate and be positively selected within the CNS [33], and that a decreased production of new T and B cells was found in a patient with PML [26], it is likely that the lower capability of naïve cells to cross the BBB may contribute to the local reduction of lymphocyte specificities recognizing mutated viral proteins, which should be a crucial prerequisite for controlling JC-virus induced PML.…”

Immunology of progressive multifocal leukoencephalopathy

“…The fact that PML patients often show strong antibody responses within the serum and the CNS compartment at onset of PML and during the course of PML (Warnke et al, 2014;Weber et al, 1997) questions the role of JCV-specific antibodies in the prevention of PML development and clearance of symptomatic JCV infection from brain. Interestingly, JCV variants with mutations in VP1 are often found in addition to prototype Mad-1 sequences in the CNS of PML patients (Gorelik et al, 2011;Reid et al, 2011). However, it is not known until now, whether mutations found in the VP1 capsid protein are driven by immune escape in order to avoid recognition by JCV-specific antibodies or whether JCV-specific antibodies are less effective because of intracellular persistence of JCV without proper exposition of JCV-encoded proteins at the cell membrane for direct antibody recognition.…”

“…VP2 and/or VP3, remains to be determined. Furthermore, the distribution of immunodominant epitopes among VP1 and the importance of VP1 mutations found in PML-associated JCV strains (Gorelik et al, 2011) with respect to immune evasion of the antibody response remain to be determined.…”

“…In contrast to urinary excreted archetypic JCV strains, PML-associated JCV genotypes and genotype variants present characteristic mutations of the major capsid protein VP1 and rearrangements of the non-coding control region (NCCR), which probably allow entry and propagation in the CNS as well as preferential tropism for glial cells or neurons (Dang et al, 2012;Gorelik et al, 2011;Major, 2010;Reid et al, 2011). Moreover, whereas archetype JCV is secreted in the urine of healthy donors and PML patients and most probably circulates in the general population, PML-associated JCV NCCR rearrangements and VP1 mutations are only found in blood and CSF of PML patients (Reid et al, 2011).…”

“…Moreover, whereas archetype JCV is secreted in the urine of healthy donors and PML patients and most probably circulates in the general population, PML-associated JCV NCCR rearrangements and VP1 mutations are only found in blood and CSF of PML patients (Reid et al, 2011). Up to date it is not clear, whether PML-associated alterations of the JCV genome occur inside or outside of the CNS and which mechanisms contribute to their occurrence or selection (Gorelik et al, 2011;Marshall et al, 2014;Reid et al, 2011).…”