Four cases of progressive multifocal leukoencephalopathy in iatrogenic immunocompromised patients

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by John Cunningham Virus (JCV). We report four PML cases in immunocompromised patients, respectively treated with (1) Natalizumab, (2) Rituximab, (3) autologous stem-cell transplantation, and (4) Tacrolimus. All patients underwent neurological examination, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), JCV-DNA research on biological samples, and lymphocytes subpopulation study. All cases presented with motor, behavioural, and cognitive disorders. Visual, sensitive, and cerebellar deficits developed in three cases. MRI revealed widespread progressive demyelinating areas with active borders; three patients presented contrast enhancement. One patient developed inflammatory reconstitution syndrome (IRIS). At MRS, all cases presented decreased N-acetyl-aspartate (NAA) and three cases showed increased choline (Cho). In one patient, plasma and urine tested positive for JCV-DNA, while cerebrospinal fluid (CSF) analysis confirmed JCV in two patients. The fourth patient had a low JCV-DNA blood titer and brain biopsy showed subacute necrosis. Two patients had abnormal lymphocyte subpopulations. Three patients underwent therapy with Mirtazapine, one of whom received Mefloquine in add-on. No clinical response was registered. Clinical onset, MRI and MRS were highly suggestive of PML in all patients, despite three cases presented contrast enhancement. In three cases JCV-DNA detection in biological samples confirmed the diagnosis. The fourth patient fulfilled diagnosis of “presumptive PML”. Our data confirm the importance to complete the diagnostic workup despite the presence of findings not completely consistent with classical PML. We hypothesize that atypical characteristics could due to the clinical conditions leading to PML

Mapping the history and current situation of research on John Cunningham virus – a bibliometric analysis

<p>Abstract</p> <p>Background</p> <p>John Cunningham virus (JCV) constitutes a family of polyoma viruses, which plays important roles in the progressive multifocal leukoencephalopathy (PML) and tumorigenesis. However, no bibliometric investigation has been reported to guide the researchers and potential readers.</p> <p>Methods</p> <p>Papers were collected from database Sci-expanded and Pubmed until May 22, 2008. The highly-productive authors, institutes and countries, highly-cited authors and journals were ranked. The highly-cited articles were subjected to co-citation and chronological analysis with highly-frequent MeSH words for co-occurrence analysis.</p> <p>Results</p> <p>Until now, 1785 articles about JCV were indexed in Sci-expanded and 1506 in Pubmed. The main document type was original article. USA, Japan and Italy were the largest three producers about JCV. Temple University published 128 papers and ranked the top, followed by University of Tokyo. Khalili K and Yogo Y became the core authors due to more than 20 documents produced. Journal of Neurovirology published more than 15 papers and ranked the top. Padgett BL and Berger JR were the first two highly-cited authors. Journal of Virology and Journal of Neurovirology respectively ranked to the first two highly-cited journals. These top highly-cited articles were divided into 5 aspects: (1) The correlation between JC virus and tumors; (2) Causal correlation of JCV with PML; (3) Polyoma virus infection and its related diseases in renal-allograft recipients; (4) Detection of JCV antibody, oncogene and its encoding protein; (5) Genetics and molecular biology of JCV. The MeSH/subheadings were classified into five groups: (1) JCV and virus infectious diseases; (2) JCV pathogenicity and pathological appearance of PML; (3) JCV isolation and detection; (4) Immunology of JCV and PML; (5) JCV genetics and tumors.</p> <p>Conclusion</p> <p>JCV investigation mainly focused on its isolation and detection, as well as its correlation with PML and tumors. Establishment of transgenic animal model using JCV T antigen would be a hopeful and useful project in the further study.</p

Natalizumab for the treatment of relapsing multiple sclerosis

Natalizumab is an α4-integrin antagonist approved as monotherapy for patients with relapsing multiple sclerosis (MS), based on demonstrated efficacy in the pivotal AFFIRM study (N = 942). Natalizumab monotherapy reduced risk of disability progression by 42%–54% and annualized relapse rate by 68% during a period of 2 years. Natalizumab was also associated with significant reductions in number of T2-hyperintense, gadolinium-enhancing, and T1-hypointense lesions and in volume of T2-hyperintense lesions (all p < 0.001) on magnetic resonance imaging. Furthermore, natalizumab-treated patients in AFFIRM experienced significant improvements from baseline in the physical and mental components of the Short Form-36 (p ≤ 0.01) and a 35% reduction in risk of clinically significant vision loss (p = 0.008 vs placebo). Natalizumab was well tolerated in phase 3 studies. Common adverse events were generally mild and included headache, fatigue, urinary tract infections, and arthralgia. Serious adverse events were similar between treatment groups. The incidence of serious hypersensitivity reactions associated with natalizumab was <1%. Progressive multifocal leukoencephalopathy was a rare complication of treatment, observed in 2 patients with MS who received natalizumab plus interferon β-1a. The robust clinical benefits of natalizumab, including benefits on patient-reported quality of life, make it an important addition to disease-modifying therapies available to patients with relapsing MS

Frequent Infection of Cerebellar Granule Cell Neurons by Polyomavirus JC in Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 HIV-positive patients. To determine the prevalence and pattern of JCV infection in GCNs we immunostained formalin-fixed, paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, glial and neuronal markers. JCV infection was detected in 30 patients (70%); 28 (93%) of these had JCV-infected cells in the granule cell layer (GCL); JCV-infected GCNs were demonstrated in 15/19 (79%) tested cases. JCV regulatory T antigen (T Ag) was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1/35 (3%) HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of T Ag over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked aspect of JCV pathogenesis in immunosuppressed individuals

Histone deacetylase inhibitors modulate human polyomavirus JC replication

M.S.M.S. Thesis. University of Hawaiʻi at Mānoa 201

Defining the Role of IP3R-Medicated ER Calcium Flux in JC Polyomavirus Infection

The human JC polyomavirus (JCPyV) persists as an asymptomatic infection in the kidneys of healthy individuals within the majority of the global population. Viral infection of JCPyV is established through peroral transmission due to poor sanitary practices. In severely immunocompromised individuals, JCPyV migrates to the central nervous system (CNS), resulting in the fatal and incurable demyelinating disease progressive multifocal leukoencephalopathy (PML). Virus-host cell interactions regulate infectious processes and influence viral pathogenesis. JCPyV attachment to host cells is mediated by α2,6-linked LSTc while internalization is mediated by 5-hydroxytryptamine serotonin type 2 receptors (5-HT2Rs). Activation of 5-HT2Rs can induce intracellular calcium (Ca2+) release upon ligand binding to activate the inositol triphosphate receptor (IP3R) signaling pathways. The goal of this project was to determine the role of intracellular Ca2+ flux in JCPyV infection. JCPyV induces Ca2+ flux from the ER almost immediately upon infection. Limiting Ca2+ release from the ER by inhibition of the IP3R with chemical antagonists significantly reduced JCPyV infection in both human kidney and brain cells, demonstrating a dependence on Ca2+ flux to regulate JCPyV infection. Although, JCPyV-induced Ca2+ flux occurs at times consistent with viral attachment and entry, analyses of these steps by flow cytometric assays, revealed that JCPyV attachment and entry were not affected by modulation of Ca2+ flux. These findings demonstrate that Ca2+ flux is regulated upon JCPyV infection and provide important insights into the activation of signaling pathways to drive the infectious process. In the future, this work can increase our understanding of PML pathogenesis and aid in the development of novel PML therapeutics

Infection by agnoprotein-negative mutants of polyomavirus JC and SV40 results in the release of virions that are mostly deficient in DNA content

<p>Abstract</p> <p>Background</p> <p>Human polyomavirus JC (JCV) is the etiologic agent of a brain disease, known as progressive multifocal leukoencephalopathy (PML). The JCV genome encodes a small multifunctional phospho-protein, agnoprotein, from the late coding region of the virus, whose regulatory functions in viral replication cycle remain elusive. In this work, the functional role of JCV and SV40 agnoproteins in virion release was investigated using a point mutant (Pt) of each virus, where the ATG codon of agnoprotein was mutated to abrogate its expression.</p> <p>Results</p> <p>Analysis of both viral protein expression and replication using Pt mutant of each virus revealed that both processes were substantially down-regulated in the absence of agnoprotein compared to wild-type (WT) virus. Complementation studies in cells, which are constitutively expressing JCV agnoprotein and transfected with the JCV Pt mutant genome, showed an elevation in the level of viral DNA replication near to that observed for WT. Constitutive expression of large T antigen was found to be not sufficient to compensate the loss of agnoprotein for efficient replication of neither JCV nor SV40 in vivo. Examination of the viral release process for both JCV and SV40 Pt mutants showed that viral particles are efficiently released from the infected cells in the absence of agnoprotein but were found to be mostly deficient in viral DNA content.</p> <p>Conclusions</p> <p>The results of this study provide evidence that agnoprotein plays an important role in the polyomavirus JC and SV40 life cycle. Infection by agnoprotein-negative mutants of both viruses results in the release of virions that are mostly deficient in DNA content.</p

Investigation of Archetype Human Polyomavirus JC Cellular Tropism and Genomic Alterations in JC Virus Pathogenesis.

Ph.D. Thesis. University of Hawaiʻi at Mānoa 2017