Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn's disease patients treated with infliximab

Bellizzi, Anna; Anzivino, Elena; Ferrari, Federica; Nardo, Giovanni Di; Colosimo, Maria Teresa; Fioriti, D.; Mischitelli, Monica; Chiarini, F.; Cucchiara, Salvatore; Pietropaolo, Valeria

doi:10.1007/s13365-011-0036-3

Cited by 25 publications

(18 citation statements)

References 44 publications

(50 reference statements)

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“…These changes may lead to acquisition of transcription factor binding sites in the NCCR that are important for pathogenesis. A recent example was described in patients receiving infliximab, where an archetype-like NCCR contained sequences that led to TATA box-associated Spi-B sites known to be important for viral replication, while JCV in the urine contained an archetype NCCR sequence (32). Additionally, as B cells mature, different transcription factors that play a role in increased viral proliferation are upregulated.…”

Section: Potential Viral Dna Recombination and Replication In Cells Omentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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SUMMARY Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.

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Section: Potential Viral Dna Recombination and Replication In Cells Omentioning

confidence: 99%

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

et al. 2012

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“…Spi-B levels are higher in cells permissive to JC virus (JCV) transcription and replication, and overexpression of Spi-B increases viral gene expression (8). Spi-B binds to target sites in the JCV noncoding control region (NCCR) isolated from PML brain tissue but not in the archetype NCCR commonly detected in the urine of asymptomatic healthy individuals (8)(9)(10)(11). Importantly, mutation of these sites in PML-associated NCCRs decreases Spi-B protein binding and viral gene expression (8,12).…”

mentioning

confidence: 99%

Lymphocyte Gene Expression and JC Virus Noncoding Control Region Sequences Are Linked with the Risk of Progressive Multifocal Leukoencephalopathy

Marshall

Ferenczy

Daley

et al. 2014

J Virol

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Progressive multifocal leukoencephalopathy (PML)-derived noncoding control region (NCCR) sequences permitted greater early viral gene expression than kidney-associated NCCR sequences. This was driven in part by binding of the transcription factor Spi-B to unique PML-associated Spi-B binding sites. Spi-B is upregulated in developing B cells in response to natalizumab therapy, a known risk factor for PML. Naturally occurring JCV sequence variation, together with drug treatment-induced cellular changes, may synergize to create an environment leading to an increased risk of PML. The incidence of progressive multifocal leukoencephalopathy (PML) has risen dramatically in recent years because of the AIDS pandemic and the increased use of immunomodulatory therapies (1). In particular, natalizumab (Tysabri; Biogen Idec), a very effective multiple sclerosis (MS) treatment, has been highly associated with PML (2).Natalizumab treatment alters the expression profiles of peripheral blood mononuclear cells (PBMCs), including the expression of the transcription factor Spi-B (3). Spi-B is required for normal B-cell receptor signaling and maturation (4-7). Spi-B levels are higher in cells permissive to JC virus (JCV) transcription and replication, and overexpression of Spi-B increases viral gene expression (8). Spi-B binds to target sites in the JCV noncoding control region (NCCR) isolated from PML brain tissue but not in the archetype NCCR commonly detected in the urine of asymptomatic healthy individuals (8-11). Importantly, mutation of these sites in PML-associated NCCRs decreases Spi-B protein binding and viral gene expression (8,12). Taken together, these results suggest that Spi-B binding to sequences in the JCV NCCR have functional effects on viral gene expression and may play a role in the activation of JCV in peripheral blood cells (13).JCV DNA has been detected in CD19 ϩ B cells and CD34 ϩ hematopoietic progenitor cells (14, 15) isolated from peripheral blood and bone marrow. These CD34 ϩ cells are strikingly increased in the peripheral blood of natalizumab-treated patients (16, 17). Immunomagnetic separation was used to isolate CD3 ϩ , CD19 ϩ , and CD34 ϩ cells from PBMCs of normal donors and MS patients treated with natalizumab. Total RNA was isolated from each cell subset, and Spi-B gene expression was measured by quantitative reverse transcription (qRT)-PCR using the endogenous control PUM1 for normalization. Spi-B gene expression was more variable in natalizumab patients. It was upregulated up to 2-fold in CD19 ϩ B cells in some patients treated with natalizumab (Fig. 1C). Spi-B expression was increased ϩ , CD19 ϩ , and CD34 ϩ cells were isolated by immunomagnetic separation from PBMC samples from patients treated with natalizumab or normal donors. The remaining cells from the separation are labeled the negative fraction. Total RNA was isolated from each fraction of cells, and the Spi-B gene expression level was measured by qRT-PCR. Spi-B mRNA levels were normalized between samples by using the endogenous control P...

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“…The active Spi-B-binding site of Mad-1/Mad-4 differs from that of CY by a single nucleotide mutation, strongly affecting the early viral gene expression [32]. Importantly, similar mutation that creates active Spi-B-binding sites adjacent to the TATA box of archetype-like JCPyV have been described by our research group in intestinal biopsies of CD patients treated with infliximab, suggesting that this mutation is supported during dissemination in the host [33]. …”

Section: Introductionmentioning

confidence: 82%

“…Moreover, a constant JC viral load value was found in intestinal biopsies during the follow-up. Therefore, although infliximab was not implicated in JCPyV reactivation directly, it seems to interfere with the fine balance between the anti-inflammatory activity of this biologic and the host immune surveillance [33]. Since the use of infliximab in CD patients blocks the TNF and interferes with the recruitment of lymphocytes causing a decreasing of interferon (IFN)-γ levels involved in the anti-viral state control, JCPyV could leave its latent state within the enteric glial cells [47] and could infect the intestinal epithelium.…”

Section: Discussionmentioning

confidence: 99%

Human Polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by immune-mediated diseases under treatment with biologics: an observational study

Bellizzi¹,

Anzivino²,

Rodio³

et al. 2013

Virol J

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BackgroundProgressive multifocal leukoencephalopathy (PML) onset, caused by Polyomavirus JC (JCPyV) in patients affected by immune-mediated diseases during biological treatment, raised concerns about the safety profile of these agents. Therefore, the aims of this study were the JCPyV reactivation monitoring and the noncoding control region (NCCR) and viral protein 1 (VP1) analysis in patients affected by different immune-mediated diseases and treated with biologics.MethodsWe performed JCPyV-specific quantitative PCR of biological samples collected at moment of recruitment (t0) and every 4 months (t1, t2, t3, t4). Subsequently, rearrangements’ analysis of NCCR and VP1 was carried out. Data were analyzed using χ2 test.ResultsResults showed that at t0 patients with chronic inflammatory rheumatic diseases presented a JCPyV load in the urine significantly higher (p≤0.05) than in patients with multiple sclerosis (MS) and Crohn’s disease (CD). It can also be observed a significant association between JC viruria and JCPyV antibodies after 1 year of natalizumab (p=0.04) in MS patients. Finally, NCCR analysis showed the presence of an archetype-like sequence in all urine samples, whereas a rearranged NCCR Type IR was found in colon-rectal biopsies collected from 2 CD patients after 16 months of infliximab. Furthermore, sequences isolated from peripheral blood mononuclear cells (PBMCs) of 2 MS patients with JCPyV antibody at t0 and t3, showed a NCCR Type IIR with a duplication of a 98 bp unit and a 66 bp insert, resulting in a boxB deletion and 37 T to G transversion into the Spi-B binding site. In all patients, a prevalence of genotypes 1A and 1B, the predominant JCPyV genotypes in Europe, was observed.ConclusionsIt has been important to understand whether the specific inflammatory scenario in different immune-mediated diseases could affect JCPyV reactivation from latency, in particular from kidneys. Moreover, for a more accurate PML risk stratification, testing JC viruria seems to be useful to identify patients who harbor JCPyV but with an undetectable JCPyV-specific humoral immune response. In these patients, it may also be important to study the JCPyV NCCR rearrangement: in particular, Spi-B expression in PBMCs could play a crucial role in JCPyV replication and NCCR rearrangement.

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Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn's disease patients treated with infliximab

Cited by 25 publications

References 44 publications

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

Lymphocyte Gene Expression and JC Virus Noncoding Control Region Sequences Are Linked with the Risk of Progressive Multifocal Leukoencephalopathy

Human Polyomavirus JC monitoring and noncoding control region analysis in dynamic cohorts of individuals affected by immune-mediated diseases under treatment with biologics: an observational study

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